C.V262 
W386p 
1913 


v  -;  • 

'. ... . 


THE 
PATHOGENESIS 

OF 
SALVARSAN  FATALITIES 


WECHSELMANN 
MARTIN 


THE 

PATHOGENESIS 


Lf 

OF 


SALVARSAN 
FATALITIES^ 


BY 


SANITAJS-RAT 
DR.  WILHELM  WECHSELMANN 

Directing  Physician  of  the  Dermatological  Department, 
Rudolph  Virchow  Hospital  in  Berlin. 


AUTHORIZED  TRANSLATION 

BY 
CLARENCE  MARTIN,  M.  D. 

First  Lieut.  M.  R.  C.,  U.  S.  Army;   Late   Clinical  Assistant 

St.  Peter's  Hospital  for  Stone  and  Other  Urinary  Diseases, 

London;    Member  Association  Military  Surgeons, 

Berlin  Urological  Society,  etc. 

ST.  LOUIS,  MO. 


THE  FLEMING-SMITH  COMPANY 

Medical   Publishers 

Saint  Louis 

U.S.A. 


Translator's 
Note. 

Just  what  role  sal- 
varsan  and  its  com- 
panion preparation, 
neosalvarsan,  are  to 
play  in  the  future 
therapeutics  of  syphi- 
lis; whether  they  are 
to  remain  the  principal 
form  of  treatment  of 
this  disease,  and 
whether  they  possess 
sufficient  spirillocidal 
power  to  warrant  their 
unaided  employment, 
are  points  that  the 
clinical  investigations 
of  Professor  Wilhelm 
Wechselmann  alone 
will  determine.  His 
vast  experience  with 
salvarsan  entitles  his 
conclusions  on  any 
phase  of  salvarsan- 
therapy  to  the  most 
respectful  considera- 
tion, and  his  investiga- 
tions into  the  causes 
of  salvarsan  fatalities 
cannot  but  add  in  large 
measure  in  fixing  sal- 
varsan's  degree  of 


toxicity  and  the  bodily 
factors  involved  in  the 
fatal  process.  Whilst 
it  is  true  that  conclu- 
sions reached  at  the 
present  time  are  sub- 
ject to  revision,  for, 
confessedly,  the  last 
word  on  salvarsan  is 
far  from  having  been 
written,  yet  it  is  safe 
to  assume  that  much 
of  our  present-day 
knowledge  of  salvar- 
san-therapy  is  sound 
and  worthy  of  reliance. 
The  translator  of  this 
little  book  believes 
that  all  physicians 
interested  in  the  treat- 
ment of  syphilis  by 
means  of  salvarsan  and 
neosalvarsan  will  find 
much  food  for  thought 
in  these  pages.  He 
hopes,  at  least,  that  the 
reader  will  see  the  au- 
thor's purpose  to  teach 
greater  caution  in  sal- 
varsan-th  e  rapy . 

Clarence  Martin,  M.  D. 

St.  Louis,  Mo.,  U.  S.  A. 
June,  1913. 


11 


COPYRIGHT.    1913 

BY 
THE    FLEMING-SMITH    COMPANY 


ON    THE    PATHOGENESIS    OF 
SALVARSAN   FATALITIES 

Of  all  the  clouds  which  have  encompassed 
salvarsan  therapy  there  yet  remains  one  to 
darken  the  horizon,  but  this  is  the  blackest, 
viz. :  the  foudroyant  fatalities  in  consequence 
of  the  intravenous  injections  of  salvarsan. 
There  cannot  be  the  least  doubt  but  that  these 
cases  are  pure  salvarsan  fatalities,  that  is,  the 
concerned  patients  would  not  have  died  at 
the  time  had  it  not  been  for  the  introduction 
of  salvarsan  into  their  veins. 

One  can  estimate  the  collateral  effects  of 
salvarsan  in  two  ways,  just  as  one  can  those 
of  any  other  sort  of  remedial  agents.  The  one 
way  is  that  the  physician  conscientiously  reg- 
ister all  of  the  untoward  effects  and  after  a 
time  present  the  ascertained  faults ;  one  is 
thereby,  as  a  matter  of  course,  convinced  that 
these  must  become  more  widely  extended  from 
day  to  day,  and  that  one,  indifferent  as  to 
whether  these  unfortunate  occurrences  offer  a 
common  type  or  not,  must  reach  the  con- 
clusion that  salvarsan  is  not  free  from  marked 
dangers.  Still  wearier  and  more  uncertain 
is  the  other  way,  that  one,  first  of  all,  free 
from  bias  follow  the  genesis  of  the  fatalities, 
prove  whether  or  not  the  same  really  should 
be  charged  against  the  agent  and  also  how 
they  may  be  avoided.  Only  the  second  is  the 
truly  scientific  way  because  it  is  free  from 
prejudice.  It  becomes  quite  clear  that  this 
way  has  led  to  a  knowledge  of  the  causes  and 


SALVARSAN     FATALITIES 

to  the  control  of  the  collateral  effects  which 
from  the  first  presented  themselves  in  the 
foreground.  What  Bessel  said  of  inaccurate 
astronomical  instruments,  holds  good  here, 
viz. :  when  one  has  an  exact  knowledge  of  an 
error,  then  it  is  an  error  no  longer. 

Along  these  lines  we  must,  therefore,  pro- 
ceed to  the  investigation  of  the  fatalities  of 
salvarsan  and  their  pathogenesis. 

It  is  best  that  we  base  our  conclusions  not 
upon  those  cases  of  death  which  have  oc- 
curred after  subcutaneous  or  intramuscular 
injections  of  salvarsan  in  persons  suffering 
from  serious  organic  changes,  but  on  the  con- 
trary upon  those  which  have  occurred  within 
a  short  time  after  injection — those  dying  in 
the  acutest  manner,  as  we  might  say — and  in 
which  no  organic  lesions  were  present.  Such 
cases  should  be  in  the  person  of  young,  healthy 
patients,  and  there  should  be  no  error  of  tech- 
nique to  influence  results. 

Millions  of  salvarsan  injections  have  been 
given  which  have  been  without  incident,  there- 
fore, a  purely  toxicologic  explanation  of  these 
fatalities  is  out  of  the  question.  Also,  by 
reason  of  the  foregoing  one  cannot  draw  a 
connection  between  the  dose  and  evil  ending. 
I  have  myself  twenty-five  times  given  in  quick 
succession  doses  of  0.6  and  0.7  without  un- 
toward collateral  effects.  Of  neosalvarsan 
1.5  has  been  administered  at  two-day  inter- 
vals without  harm.  But  on  the  other  hand, 
is  the  single  fatal  ending  occurring  in  my  de- 
partment, which  took  place  in  the  case  of  a 
young  girl,  who  had  received  0.1  and  0.2  of 
old  salvarsan.  The  other  fatalities  also  fol- 

—  8  — 


SALVARSAN     FATALITIES 

lowed  the  usual  doses.  One  might  think  that 
this  bad  luck  resulted  from  a  preparation 
which  had  undergone  decomposition  changes, 
but  Ehrlich  himself,  more  than  once  has  sent 
me  supplies  of  salvarsan  made  under  the  same 
circumstances  as  that  which  has  caused  death, 
and  yet  when  used  in  my  hands  no  evil  re- 
sults followed.  Still  more  clearly  demonstra- 
ble of  this  fact  is,  that  in  our  case  a  three 
gram  tube  had  been  made  into  solution,  from 
which  a  series  of  patients  received  0.5  and  0.6 
without  reaction,  while  the  girl  who  died,  and 
into  whom  was  injected  the  identical  solution, 
received  but  0.2.  Portner  had  a  similar  ex- 
perience, injecting  four  patients  with  a  solu- 
tion made  from  the  same  tube  and  yet  but 
one  became  ill  and  died.  Querat  injected  eight 
patients  from  a  common  mixture,  and  again 
only  one,  the  fourth  injected,  an  apparently 
healthy  young  man,  succumbed,  death  ensuing 
after  a  few  hours.  Thus  it  is  sure  that  the 
drug  in  itself  did  not  cause  death;  the  deter- 
mining cause,  therefore,  for  the  deadly  ac- 
tion must  lie  within  the  patient  himself. 

A  hazily  outlined  hypothesis  of  a  hypersen- 
sitiveness  has  been  offered  in  the  way  of  an 
explanation.  Now  this  explanation  would 
have  value  were  we  able  to  correctly  estimate 
this  hypersensitiveness  in  a  clinical  manner, 
for  then  before  the  injection  of  salvarsan  we 
could  preserve  the  patient  from  the  unhappy 
termination.  On  the  post-mortem  table  this 
hypersensitiveness  has  a  worthless  patholog- 
ical significance,  and,  therefore,  according  to 
its  very  nature — it  could  have  only  a  relative 
clinical  value — it  must  be  held  to  be  entirely 


8ALVAR8AN     FATALITIES 

unacceptable.  Then  it  must  also  be  rememb- 
ered that  the  theory  of  hypersensitiveness  be- 
comes still  further  weakened  by  the  fact  that 
in  the  majority  of  instances,  the  patients  who 
succumbed  to  salvarsan  did  not  die  after  the 
first  injection,  but,  on  the  contrary,  irregularly 
after  subsequent  ones,  usually  after  the  sec- 
ond. Also  there  could  not  be  established  the 
least  connection  between  the  hypersensitive- 
ness  and  the  dose  employed,  in  evidence  of 
which  may  be  introduced  the  case  of  Kliene- 
berger.*  A  pregnant  waitress,  25  years  of 
age,  received  on  March  29th  an  intragluteal 
injection  of  0.2;  on  April  3rd  she  was  given 
1.2  intravenously.  Apart  from  an  urticarial 
eruption  radiating  from  the  site  of  injection, 
and  a  temperature  38.  (100.5  Fahr.),  she 
bore  this  large  dose  well.  On  the  22nd  of  May 
she  was  given  another  injection  of  0.6  where- 
upon the  usual  indications  of  salvarsan  badly 
tolerated  set  in,  and  on  May  25th  death  took 
place. 

One  is  not  justified  in  employing  the  theory 
of  cumulative  action;  I  have  myself  given  0.6 
doses  at  two  and  three  day  intervals,  ten  or 
fifteen  times,  without  any  evil  collateral  ef- 
fect. These  cases  showed  no  cumulative  ef- 
fects. On  the  other  hand,  in  most  instances, 
death  has  followed  after  a  total  dose  of  from 
0.3  to  0.8. 

This  confusion  is  further  added  to  by  the 
pathological  findings  which  reveal  in  a  great 
number  of  cases  a  hemorrhagic  encephalitis. 
For  that  reason  one  was  disposed,  in  consider- 


*Deutsche  med.  Wochensch.,  1912,  No.   36. 
—  10  — 


SALVARSAN     FATALITIES 

ing  the  nervous  manifestations  produced  by 
salvarsan,  to  locate  the  site  of  the  hypersen- 
sitiveness  in  the  central  nervous  system,  and 
was  prone  to  speak  of  congestion  of  the  brain. 
Potzl  and  Schiiller  who  have  observed  the 
same  brain  congestion  after  the  employment 
of  mercury,  give  the  following  explanation: 
"The  consequences  of  the  early  luetic  infec- 
tion manifest  themselves  in  a  permanent 
change  of  balance  between  intracranial  and 
extracranial  circulation,  as  a  result  of  which 
there  may  be  an  increased  susceptibility  of  the 
brain  to  toxic  influences.  The  brain  then 
plays  a  more  important  role  in  the  reaction  to 
toxic  influences  of  various  sorts  than  under 
normal  circumstances."  The  most  that  one 
can  say  about  this  explanation  is  that  it  is 
purely  hypothetical.  Were  this  hypothesis 
correct  it  would  still  be  difficult  to  understand 
why,  with  the  well  known  extraordinarily  fre- 
quent participation  of  the  brain  and  meninges 
in  the  syphilitic  process,  a  hypersusceptibility 
to  mercury  is  so  rarely  seen.  That  this  super- 
sensitiveness  to  salvarsan  is  seen  so  dispro- 
portionately oftener  indicates  in  itself  that  in- 
fluences other  than  brain  syphilis  enter  into 
the  question.  Then  add  to  this  point  that,  in 
many  salvarsan  fatalities,  the  brain  is  found 
to  be  entirely  free  from  luetic  or  other 
changes ;  furthermore,  no  illuminating  con- 
nection can  be  seen  in  the  age  of  the  infection, 
for  the  most  casual  inspection  of  statistical 
information  shows  that  syphilitics  in  all  stages 
of  the  disease  have  met  with  this  sad  fate. 
That  the  notion  of  a  neurotoxic  action  is  quite 
untenable  is  evident  in  the  fact  that  even  in 

—11  — 


8ALVARSAN     FATALITIES 

the  presence  of  encephalitis  hemorrhagica  fol- 
lowing salvarsan,  the  brain  substance  does  not 
seem  to  be  affected  (still  further  proven  by 
Nissl's  thorough  examination  of  the  cells)  ; 
on  the  contrary,  it  is  solely  the  blood  vessels 
which  are  damaged.  That  these  vessel  lesions 
are  caused  by  noxious  influences  of  a  general 
character  is  shown  by  demonstrable  hyper- 
emia  and  hemorrhage  in  all  of  the  inner  or- 
gans. 

Especially  since  I  have  myself  experienced 
a  fatality  in  consequence  of  the  new  therapy, 
I  can  look  at  the  problem  all  the  more  sharp- 
ly; therefore  in  presenting  my  case  I  shall 
give  every  point  in  connection  with  it. 

Marie  St.,  born  on  November  21st,  1887,  re- 
ceived in  the  hospital  February  26th,  1912.  The 
patient  has  always  been  well,  knew  nothing  of 
her  infection  and  has  not  been  treated.  Small 
papular,  universal  rash.  Plaques  on  the  tonsils. 
Wassermann  +  +  +  +.  For  two  weeks  has  suf- 
fered with  headache,  sleeplessness,  and  tinnitus 
on  the  left  side;  according  to  the  aural  examina- 
tion the  tympanic  membranes  of  both  sides  are 
involved,  but  the  findings  do  not  reveal  any  lesion 
commensurate  with  the  difficulty.  Examination 
of  the  eyes  reveals  a  nystagmus  claimed  to  have 
existed  for  six  years;  a  sister  suffers  from  the 
same  disorder.  The  retina  is  normal.  Vision  5/5. 
Urine  normal.  Lumbar  puncture  on  February 
27th,  marked  by  a  forcible  escape  of  fluid.  Fluid 
spurts  out  in  a  stream.  Cells  ++,  gold  +  +  , 
Nonne  — ,  Wassermann  — .  On  March  1st,  vomit- 
ing. From  March  6th  to  March  18th  patient  was 
rubbed  daily  with  4  grams  of  ungt.  hydr.  On 
March  12th  the  patient  received  0.1  salvarsan  in 
an  alkaline  solution  (0.9  per  cent,  salt  solution). 
Borne  without  reaction;  temperature  37.6  (99.7 
Fahr.).  March  13th  temperature  38  (100.4  Fahr.). 
Thenceforth  temperature  normal.  On  March  18th, 

—  12  — 


SALVARSAN     FATALITIES 


0.2  salvarsan  with  immediate  rise  of  temperature 
to  40.3  (104.5  Fahr.);  headache  and  vomiting; 
angina  and  swelling  of  the  glands  of  the  throat. 
Following  the  administration  of  0.3  (5  grs.)'  of 
pyramidon  the  temperature  falls  slowly;  on  the 
morning  of  the  20th  temperature  36.4  (97.5  Fahr.). 
Six  o'clock  in  the  evening  general  convulsions 
suddenly  appear  with  biting  of  the  tongue.  The 
pupils  are  widely  dilated  and  do  not  react,  coma, 
marked  respiratory  distress  with  deep  contrac- 
tion of  the  jugular,  no  cyanosis,  trismus  and 
rigidity  of  the  extremities.  On  March  21st,  the 
advisability  of  trepanation  considered,  but  as 
there  are  no  evidences  of  brain  pressure  (pulse 
120,  soft),  the  idea  is  set  aside  and  a  venesection 
made,  200  c.c.'  of  blood  being  abstracted  and  then 
a  saline  infusion  of  300  c.c.  given.  Patient  is 
unconscious.  No  rigidity  of  the  neck  or  of  the  limbs ; 
reflexes  present;  respiration  free  but  groaning. 
Temperature  in  anus  40.7  (105.2  Fahr.).  Corneal 
reflex  weak,  pupils  just  a  bit  dilated,  right  slightly 
more  so  than  left,  react  promptly,  motility  cannot 
be  tested,  retina  mildly  hyperemic,  veins  some- 
what distended  and  very  dark.  Cyanosis  of  the 
retina  but  no  hemorrhage,  no  circumscribed  area, 
no  iritis.  Function  of  the  bladder  not  observed. 
By  means  of  a  catheter  a  small  quantity  of  urine 
has  been  evacuated;  this  contains  much  albumin, 
numerous  granular  casts  and  formed  elements. 
Without  any  other  changes  death  ensued  at  5 
o'clock  in  the  afternoon.  Spinal  fluid  abstracted 
shortly  after  death  coagulated  spontaneously  like 
gelatine.  Nonne  +  +  +  +  ,  gold  +  +  +  (10-5000 
white)  cells  +  +  +,  lymphocytes:  leucocytes  8:1, 
Wassermann  5  per  cent.  ++,  100  per  cent. 

AUTOPSY    (Dr.  Auffermann). 

Brain. — No  changes  are  to  be  recognized  in  the 
skull.  The  dura  mater,  especially  in  the  hind 
segment,  is  firmly  attached  to  the  skull.  Veins 
and  sinuses  distended  with  blood.  The  inner  sur- 
face of  the  dura  mater  is  covered  with  irregular 
arterial  hemorrhages,  arranged  in  stripes  of  a 
bright  red  color.  The  more  delicate  meninges  to 

—  13  — 


8 ALVARS AN     FATALITIES 


a  site  between  the  optic  nerve  and  the  olfactory 
tract  in  front  of  the  chiasma,  are  transparent. 
The  veins  are  markedly  filled  with  blood.  The 
brain  substance  is  of  a  somewhat  compact  con- 
sistence; no  gross  changes  are  present.  The  ar- 
teries of  the  base  are  reddish  blue  and  quite  uni- 
formly thickened.  At  either  side  of  the  crus 
cerebri  and  somewhat  over  it  the  meninges  are 
hemorrhagic. 

Spinal  Cord. — Everywhere  the  nerve  tracts  are 
freshly  hemorrhagic;  the  hemorrhages  extend  to 
between  the  vertebrae.  The  blood  vessels  of 
the  cord  are  distended.  The  coverings  of  the  cord 
opposite  the  middle  and  upper  dorsal  vertebrae 
are  somewhat  congested.  The  substance  of  tne 
cord  is  rather  firm;  its  appearance  is  nowhere  out 
of  the  ordinary.  The  fluidity  of  the  cerebrospinal 
fluid  is  not  increased.  On  the  posterior  surface 
are  rather  firm  adhesions  between  dura  and  pia 
mater. 

Pharyngeal  Organs. — These  are  somewhat  uni- 
formly swollen.  The  palatine  tonsils  are  larger 
than  a  bean. 

Thorax. — Position  of  diaphragm,  on  the  left 
fifth,  on  the  right  fourth  rib. 

Heart. — The  pericardium  shows  nothing  of  in- 
terest. The  heart  is  rather  larger  than  the  fist. 
The  ventricles  are  contracted.  The  epicardium 
over  the  vessels  thickened  moderately.  In  the 
myocardial  substance  are  to  be  seen  golden  and 
grayish  brown  stringy  streaks,  and  very  numer- 
ous striped,  dark  red  foci  of  the  diameter  of  1 
mm.  but  without  a  sharply  defined  border.  Be- 
neath the  endocardium  of  the  left  ventricle  are 
confluent  red  specks.  The  valves  are  intact. 

Lungs. — A  few  fibrous  areas  are  seen  in  the 
covering  of  the  right  lung.  The  left  pleura  is 
normal.  Both  lungs  are  rather  hemorrhagic  and 
lymphedematous,  besides  they  are  studded  with 
air-free  foci  of  the  size  of  a  hazel  nut.  some  of 
which  are  confluent.  These  foci,  through  their 
lighter  color  and  more  solid  consistency,  are  quite 
distinct  from  the  adjacent  lung  tissue. 

—  14  — 


8ALVAR8AN     FATALITIES 


ABDOMINAL   CAVITY. 

Stomach. — Mucosa  slightly  swollen.  There  are 
extensive,  light  red  hemorrhages  in  the  folds  of 
the  upper  curvature;  these  are  made  up  of  small, 
distinct  foci. 

Bowel. — On  the  valves  of  the  large  intestines 
appear  irregularly  distributed  hemorrhages,  dn 
connection  with  which,  here  and  there,  are  ulcera- 
tions  of  the  mucosa.  The  follicles  are  slightly 
swollen. 

Spleen. — 14x91/ox4  cm.  Consistence  rather  firm. 
No  alteration  in  structural  appearance.  Follicle 
swollen  moderately. 

Liver. — Somewhat  enlarged.  Capsules  thickened. 
Consistence  soft.  Structure  indistinct. 

Kidneys. — Enlarged.  Capsule  easily  detachable; 
contains  on  the  inner  surface  several  hemorrhages 
of  the  size  of  a  pin  head.  Surface  of  the  kidney 
even.  Cortex  thickened,  structural  appearance  not 
distinct.  Color  grayish  red.  The  pyramids,  which 
are  also  swollen  in  a  marked  manner,  are  filled 
in  their  lower  third  with  yellowish  white  streaks. 

Pancreas. — Firm,  no  change  in  structural  ap- 
pearance. 

Suprarenal  Bodies. — Unchanged. 

Pelvic  Organs. — No  change  in  rectum.  Posteri- 
orly in  Douglas's  pouch  numerous  old  adhesions. 
Uterus  and  ovaries  in  state  of  menstruation. 

Dr.  Bielschowsky's  microscopical  investiga- 
tion of  the  brain  disclosed  no  noteworthy  al- 
terations which  the  clinical  picture  could  ex- 
plain. Sections  from  the  cerebral  cortex,  the 
pons  and  the  medulla  were  examined.  In  none 
were  inflammatory  changes  found.  Occasional 
pyramidal  cells  from  the  cerebral  cortex  pre- 
pared after  Nissl's  method,  presented  signs  of 
a  slight  swelling  with  beginning  chromatoly- 
sis.  However,  this  finding  is  entirely  without 
significance  and  could  easily  have  had  its  ori- 
gin coincident  with  death.  Probably  a  note- 

—  15  — 


SALVARSAN     FATALITIES 

worthy  point  is  the  normal  condition  of  the 
blood  vessel  walls.  Hemorrhages  are  not  pres- 
ent. Microscopical  examination  of  the  other 
organs  by  Prof.  Pick  discloses  the  following: 
Section  from  alcohol-hardened  kidney,  stained 
with  hemalaun-eosin,  shows :  the  epithelium  of 
the  tubuli  contorti  of  the  first  order,  is  vari- 
ously swollen,  cloudy  with  fine-grained  strati- 
fications, with  indistinct  boundary  toward  the 
lumen.  Still  oftener  in  these  cells  the  nuclei 
are  missing  (necrosis).  In  the  lumen  fine- 
grained coagulated  contents.  The  epithelium 
of  the  tubuli  contorti,  second  class,  as  well  as 
that  of  the  collecting  tubules  seems  to  be 
free  from  changes.  No  calcareous  deposits  in 
any  form  were  to  be  found  in  the  specimens 
examined.  The  stroma  of  the  cortical  layer 
between  the  injured  tubuli  uriniferi  is  some- 
what increased,  slightly  edematous,  noticeably 
proliferated.  Fresh  small  cell  infiltration  foci 
are  lacking.  In  the  glomeruli  is  apparently 
an  increase  of  nuclear  elements. 

In  general,  therefore,  a  subacute  parenchy- 
matous  and  interstitial  nephritis. 

Dr.  Auffermann  made  a  special  examination 
of  the  kidneys,  and  concerning  the  microscop- 
ical stripes  in  the  pyramids,  established  the 
following : 

Microscopically,  in  a  subdued  light,  the  yellow 
stripes  appear  as  dark,  fairly  homogenous  casts 
which  correspond  to  the  site  of  the  straight  urin- 
iferous  tubules.  They  do  not  dissolve  with  the 
addition  of  hydrochloric  acid,  nor  is  there  genera- 
tion of  gas.  Fixation  in  formalin  caused  them  to 
dissolve,  but  in  denatured  alcohol  in  great  part 
they  remain  unchanged.  Paraffine  sections  were 
treated  with  the  usual  nucleus  and  connective  tis- 

—  16  — 


SALVARSAN     FATALITIES 


sue  stains.  These  showed  severe  damage  to  the 
epithelium  as  well  as  to  the  tubular  systems,  as 
the  glomeruli  and  their  capsules.  Neither  infil- 
tration nor  interstitial  or  blood  vessel  change^ 
could  be  found.  The  nature  of  the  yellow  casts 
was  as  follows:  They  appeared  entirely  amorphous 
without  any  tendency  toward  crystalization,  and 
did  not  stain  with  hematoxylin.  With  nitrate 
of  silver  they  became  of  an  intensely  black  color, 
and  also  occupied  the  site  of  the  epithelia.  The 
latter  now  became  only  partially  recognizable. 
Notwithstanding  the  contradictory  condition  I 
would  claim  the  casts  to  be  of  phosphatic  nature. 
The  circumstance  that  they  did  not  appear  to 
dissolve  when  treated  with  hydrochloric  acid 
might  be  attributed  to  an  error  on  my  part  in 
abbreviating  the  period  of  observation.  Their 
solubility  in  formalin — formic  acid — demonstrates 
this.  According  to  the  literature  biliary  pigment 
and  uric  acid  are  likewise  excreted. 

Examination  of  the  liver  and  heart  disclosed 
no  special  condition  (Sections  hardened  in  al- 
cohol, stained  as  usual). 

The  chemical  examination  (Prof.  Loeb) 
shows  in  blood :  Blood  sugar  0.089  per  cent., 
free  nitrogen  (Holweg)  0.0174  per  cent,  iron 
0.210  per  cent.,  total  nitrogen  1.454  per  cent, 
therefore  marked  increase. 

Kidneys:  Arsenic  plainly  demonstrable. 
Mercury  very  plainly  demonstrable. 

Brain:  Arsenic  plainly  demonstrable.  Only 
a  slight  trace  of  mercury. 

Feces:  Arsenic  demonstrable  in  slight 
traces;  no  mercury. 

The  cerebrospinal  fluid  contains  0.05  per 
cent,  arsenic. 

The  spontaneous  gelatinous  coagulation  of 
the  cerebrospinal  fluid  drawn  off  immediately 
after  death,  was  most  extraordinary.  The 

—  17  — 


SALVARSAN     FATALITIES 

significance  of  this  condition  is  not  yet  suffi- 
ciently explained.  In  this  connection  it  may 
be  added  that  Mestrezat  has  made  a  study  of 
this  question.  (Le  liquide  cephalorachidien, 
Paris,  1912,  p.  425.) 

Here  I  would  remark  that  neither  in  arsenic 
poisoning  nor  in  uremic  coma  is  there  any 
mention  of  this  interesting  condition.  (In 
reference  to  this  compare  the  Thesis  by 
Petit,  Meningite  et  reactions  mcningces  dans 
I'uremie,  Paris,  1912,  Declose.)  The  special, 
extraordinary  terminal  changes  of  the  liquor, 
in  part,  must  well  have  some  connection  there- 
with. 

An  entirely  incorrect  recital  of  a  case  was 
offered  at  the  July  meeting  of  the  Dermato- 
logical  Society,  this  being  the  history  of  a  case 
which  had  been  twice  injected  by  Dr.  Portner 
and  which  died  in  my  department. 

Portner  gave  me  the  following  history : 

"Franz  Ro.,  37  years  old.  At  the  beginning  of 
April,  1912,  infected  with  syphilis.  Hard  chancre. 
May  21st  Wassermann  was  made  by  Dr.  Meier. 
Positive.  One  injection  of  mercury.  On  May  24th 
given  intravenous  injection  of  0.4  salvarsan.  Am- 
bulatory patient.  It  is  claimed  that  after  the  in- 
jection diarrhea  set  in,  and  after  several  days  a 
feeling  of  faintness.  Then  came  a  return  to  nor- 
mal. 

On  June  13th  another  injection  of  0.4  salvarsan 
(Dr.  Weber).  This  was  unattended  by  trouble. 
Patient  was  not  taken  into  hospital.  After  injec- 
tion a  very  severe  pain  seized  patient  in  wrist 
and  ankle  joints.  The  affected  limbs  could  scarce- 
ly be  moved.  After  a  morphine  injection  (Dr. 
Steinitz)  pain  slightly  moderated.  Dr.  Steinitz 
found  patient  in  severe  collapse,  strongly  acceler- 
ated, scarcely  perceptible  pulse.  Ordered  camphor. 
Fever  present.  Patient  is  an  inveterate  smoker. 

—  18  — 


SALVARSAN     FATALITIES 


Large,  corpulent  man.  Face  flushed  with  fever. 
Expression  of  face  indicative  of  suffering.  On 
both  thighs  marked  diffuse  reddening  of  the  skin. 
On  the  left  thigh  the  redness  at  the  knee'  is  in 
sharp  contrast  to  the  strikingly  pale  blue  color  of 
the  lower  leg.  The  toes  of  the  left  foot  are 
cyanotic.  The  left  hand  also  shows  from  the 
wrist  downwards  the  same  pale  blue,  lightly 
cyanotic  coloring.  Here  as  on  the  foot  the  blue 
color  is  most  marked  at  the  finger  tips.  Pulse  is 
very  much  accelerated  and  scarcely  perceptible. 
Temperature  38.8  (101.8  Fahr.).  No  appetite. 
Therapy:  Coffee  every  two  hours;  hot  hand  baths; 
hot  packs  to  the  feet. 

June  15th,  1912.  Hand  pale  blue,  but  color,  in 
general,  not  so  pale  as  yesterday.  But  the  pale 
blue  color  on  the  lower  leg  is  still  strongly  marked. 
As  before,  the  toes  are  still  cyanotic.  Pain  in  the 
left  hand  and  in  left  wrist  joint  in  the  reclining 
posture  is  somewhat  less.  At  an  attempt  to  move 
the  joint  the  patient  cries  out  at  once.  Both  thighs 
are  brilliantly  red. 

Patient  feels  very  weak.  Occasionally  tries  to 
arise  from  bed  hoping  to  find  relief,  but  staggers 
and  must  again  lie  down.  Pulse  very  small, 
scarcely  perceptible,  strongly  accelerated.  Tem- 
perature 39.5  (103.1  Fahr.).  More  frequent  vomit- 
ing and  difficulty  of  defecation.  Upon  taking 
nourishment  (milk)  vomiting  sets  in  afresh. 
Highly  smelling  urine,  light  in  color,  turbid,  trace 
of  albumin. 

N.  B. — On  June  13th,  three  other  patients  were 
injected  with  the  same  preparation,  dose  likewise 
0.4.  Well  borne  except  in  the  case  of  a  19-year-old 
anemic  girl,  who  vomited  lightly  two  or  three 
times." 

I  proposed  to  Dr.  Portner  that  after  the 
conclusion  of  my  investigations  we  publish 
the  case  together,  but  he  did  not  trouble  him- 
helf  to  describe  the  case  according  to  the  in- 
formation he  had,  so  the  result  was  that  he 
erred  in  needlessly  burdening  the  literature 

—  19  — 


8ALVARSAN     FATALITIES 

and  further  the  discussion  had  to  be  conducted 
along  false  channels. 

The  report  coincided  in  essentials  with  that 
which  was  published  by  Portner  in  the  Der- 
matol.  Zeitschr.,  Bd.  XIX,  No.  12.  There 
Portner  says  that  he  made  two  further 
injections  with  the  same  solution  which  he 
employed  in  the  case  of  the  above  mentioned 
patient,  and  that  no  untoward  results  occurred. 
Then,  he  adds  thereto  (1  .c.  p.  1091)  :  "In 
the  Virchow  Hospital  evidently  a  trepanation 
was  undertaken  in  the  case,  well  according 
with  the  proposal  of  Ehrlich  that  in  cases  of 
encephalitis  after  salvarsan,  this  operation  be 
attempted." 

The  patient's  history  and  our  findings  put 
the  case  in  an  entirely  different  light. 

On  admission  into  the  hospital  on  June  15th, 
patient  is  somewhat  stupified  and  has  headache. 
Nine  years  ago  underwent  a  course  of  mercurial 
inunctions  with  Dr.  Schmilinski.  A  week  after 
the  first  injection  the  patient  felt  bad.  Vomiting 
and  chills. 

The  upper  half  of  the  face  and  the  forehead  are 
covered  with  a  relapsing  erythema.  Slight  con- 
junctivitis. The  left  arm  is  lame,  the  left  leg 
is  paretic,  but  can  be  raised  up.  Urine  dark 
brown;  retention  necessitates  catheter;  bowel 
movement  black  and  paplike.  Patient  vomits  black 
masses.  Patellar  reflex  present.  Right  pulse  soft, 
120;  left  cannot  be  felt  in  the  brachial. 

Condition  remains  unchanged.  Urine  contains 
albumin  and  granular  casts.  Lumbar  puncture  on 
June  16th  affords  no  relief.  Nonne  +,  G  +, 
C  +,  Wassermann  500  per  cent  — .  Vomiting 
black  masses.  Patient  is  stupified,  but  no  coma, 
no  convulsions.  With  ascent  of  temperature  to 
38.4  (101.1  Fahr.),  and  increasing  cardiac  weak- 
ness, death  came  at  9  o'clock  on  the  morning  of 
June  17th. 

—  20  — 


SALVARSAN     FATALITIES 


Arsenic  in  the  urine  and  vomitus  in  abund- 
ance (Prof.  Loeb). 

Through  questioning  the  patient's  wife  the  his- 
tory of  the  case  was  completed  as  follows:  In- 
fection nine  years  ago,  after  which  one  inunction 
course  which  was  repeated  a  year  later  on  ac- 
count of  manifestations  in  the  region  of  the  neck. 

Patient  very  intemperate,  drinking  daily  12  to 
15,  occasionally  40  glasses  of  beer  and  whiskey. 
Inveterate  smoker.  At  the  beginning  of  May  he 
came  under  Dr.  Portner's  care  by  reason  of  small 
blisters  appearing  on  the  glans  penis.  After  the 
first  injection  on  May  24th,  he  became  indisposed 
on  May  30th.  Chills  on  June  1st.  Congestion  of 
the  eyes.  In  spite  of  his  condition  he  went  to 
the  race  course  on  June  2nd.  On  the  same  day 
a  red  eruption  broke  out  on  the  legs,  arms  and 
trunk.  Then  followed  dizziness  and  weakness. 
Immediately  after  the  second  injection  on  June 
13th,  the  patient  became  very  much  distressed  and 
vomited  freely.  He  complained  that  the  injec- 
tion had  been  very  painful.  On  the  same  day  an 
assistant  who  was  called  into  the  case  confirmed 
the  absence  of  pulsation  in  the  left  arm.  Patient 
dragged  himself  about  until  3  o'clock  in  the  after- 
noon but  gave  up  at  four;  the  left  hand  and  foot 
became  ice  cold  and  the  site  of  agonizing  pains. 
Dr.  Steinitz  had  to  give  morphine,  but  notwith- 
standing this  the  pains  continued  to  be  extremely 
severe.  Patient  was  very  excited  and  wanted  to 
kill  himself. 

Besides  she  reported  what  the  patient  had 
told  her,  that  some  years  before  he  had  been 
operated  upon  by  Gen.  Rat.  Korte  for  epilepsy. 
The  previous  history  so  cheerfully  put  at  my 
disposal,  runs  as  follows: 

During  a  brawl  on  the  night  of  June  13th,  1904, 
he  sustained  a  blow  with  a  cane  which  injured 
the  right  side  of  the  skull.  The  injury  was  dressed 
at  a  public  dispensary.  On  June  18th  convulsions 
for  the  first  time  seized  the  patient;  during  the 
course  of  the  night  and  until  noon  of  the  next  day 

—  21  — 


SAL VAR8 AN     FATALITIES 


he  had  five  seizures.  Brought  to  the  hospital  by 
the  ambulance  at  5  o'clock  on  the  afternoon  of 
June  19th. 

Immediately  after  admission  a  convulsion  oc- 
curred which  was  closely  observed  by  the  medical 
man  in  charge.  Patient  draws  left  arm  to  the 
side  with  light  convulsive  movements,  while  at 
the  same  time,  with  the  pupils  dilated,  the  head 
is  strongly  drawn  toward  the  left.  Patient  is  un- 
conscious; general  convulsions  have  set  in.  The 
mouth  is  widely  opened,  tongue  remains  behind 
''  the  teeth.  Lasts  for  a  period  of  three-quarters  of 
a  minute.  Following  is  a  light  comatose  state. 

The  examination  discloses  two  wounds  in  the 
region  of  the  parietal  bone,  one  of  which  runs  in 
a  straight  line  from  front  towards  the  back  for 
an  extent  of  3  cm.  In  front  of  this  is  an  irregular 
wound  connected  with  two  skin  fissures  which 
join  one  another.  The  length  of  the  single  wound 
is  about  1%  cm.  Near  the  first  described  lacera- 
tion is  a  superficial  cut  1%  cm.  long  which  the 
patient,  upon  the  recovery  of  consciousness,  says 
is  an  incision  made  by  the  attending  physician. 
The  wounds  are  matted  with  hair,  and  dressed 
with  iodoform  gauze.  The  borders  of  the  wounds 
are  slightly  reddened.  Abrasions  of  the  front  half 
of  the  head.  Cleansed  with  alcohol  and  ether. 
Dressed  with  iodoform  gauze. 

Pulse,  72,  respiration  easy.  The  patient  regains 
consciousness  soon  after  the  affair  and  gives  a 
good  account  of  the  circumstances  of  injury. 

During  the  night  had  three  convulsive  seizures 
of  the  character  described  above;  similarly  dur- 
ing the  physician's  morning  rounds  between  8  and 
8:30.  Patient  received  morphine  0.01  (1/6  gr.), 
following  which  improvement  immediately  takes 
place  as  on  yesterday  evening  (June  19th). 

A  pronounced  paralysis  of  the  left  facial  nerve 
is  present.  The  gross  motor  power  of  the  left 
arm  is  plainly  reduced.  The  tongue  when  ex- 
tended deviates  slightly  towards  the  left. 

In  the  parietal  region  are  three  wounds.  The 
one  in  front  extends  to  the  bone,  but  apparently 
the  others  do  not.  Employment  of  a  crescent- 
shaped  incis^oj^  with  highest  point  of  incision  on 

—  22  — 


SALVARSAN     FATALITIES 


line  with  parietal  suture,  base  over  the  parietal 
bone;  soft  parts  are  elevated  with  profuse  hemor- 
rhage. Corresponding  with  the  anterior  wound, 
close  by  the  sagittal  suture,  is  a  defect  in  the  bone, 
about  the  size  of  a  25  cent  piece,  with  deeply  de- 
pressed base  and  edges;  between  the  splinters  of 
bone  are  blood  coagula  filling  up  the  site  of  the 
injury.  Numerous  hairs  are  in  wound.  Inoccula- 
tion  shows  staphylococcic  infection. 

Operation. — Circling  the  fracture,  the  edge  of 
the  bone  is  beveled  with  a  chisel.  Three  large  and 
numerous  small  deeply  depressed  fragments  of 
the  external  table  are  removed.  Adherent  hair 
may  also  be  seen  on  these  pieces  of  bone.  Moderate 
extravasation  of  blood  between  bone  and  dura. 
Removal  of  all  splinters  together  with  thorough 
cleansing  of  wound.  Tamponed  with  iodoform 
gauze. 

At  seven  o'clock  on  June  20th,  an  epileptiform 
attack,  resembling  the  former  one,  except  that 
head  is  turned  toward  the  right. 

Afternoon  of  June  21st:  The  patient  feels  bet- 
ter; the  facial  paralysis  about  gone;  patient  com- 
plains of  burning  in  the  operation  wound. 

Morning  of  June  22nd:  Patient  slept  well; 
dressing,  which  yesterday  had  to  be  renewed,  has 
not  again  become  saturated;  very  slight  paralysis 
of  the  facial;  the  left  eye  can  be  entirely  closed; 
tongue  still  deviates  a  little  towards  the  left. 

A  difference  in  the  gross  muscular  power  of  the 
two  arms  is  present  in  a  minimum  degree. 

No  lameness  in  legs;   pain  entirely  gone. 

Senses  clear.  Urine  golden  yellow,  clear,  con- 
tains no  albumin. 

On  the  22nd  of  June,  at  midday,  marked  von- 
vulsize  seizure. 

On  the  24th  at  9:20  in  the  morning,  convulsion 
affecting  mainly  the  left  side  of  the  body. 

June  25th,  during  the  night  at  12:15  and  12:20, 
further  severe  convulsive  attacks. 

Removal  of  the  tampon,  wound  disinfected,  re- 
dressed. Patient  complains  of  anxious  feeling  and 
dizziness. 

June  29th:  No  convulsive  attack  since  removal 
of  the  tampon.  Very  slight  paralysis  of  the 
left  facialis. 

—  23  — 


SALVARSAN     FATALITIES 


July  12th:  Patient  again  twice  had  slight 
twitching  of  the  left  arm.  Medication:  Kal.  brom. 
1  gram  (15  grs.)  three  times  daily. 

July  24th:  The  wound  is  almost  closed;  dress- 
ing of  nitrate  of  silver  salve.  Patient  feels  quite 
well;  no  suspicion  of  any  paroxysm;  no  dizziness; 
no  convulsions.  Under  close  examination  twitch- 
ing in  left  leg.  In  the  bone  is  a  large  defect,  in 
which  the  pulsation  of  the  brain  may  be  clearly 
felt  and  seen. 

According  to  information  given  by  the  wife, 
since  the  time  above  mentioned,  the  patient  re- 
mained free  from  epileptic  convulsions. 

Post-mortem  immediately  after  death  (Geh. 
Rat.  v.  Hansemann)  shows  the  following: 

Anatomical  Diagnosis. — Partial  defect  of  calvar- 
ium.  Yellow  softening  of  brain.  Pulmonary  em- 
physema. Thrombosis  of  the  left  radial  artery. 
Hepatitis,  fatty  infiltration.  Parenchymatous  ne- 
phritis. Subendocardial  hemorrhage,  also  of  the 
mucosa  of  the  jejunum. 

Trunk  and  Extremities. — Strongly  built  male 
body  with  well  developed  musculature  and  mod- 
erate deposit  of  fat  Over  the  entire  body,  particu- 
larly left  arm,  bright  red,  irregularly  outlined 
spots. 

The  radial  artery  in  front  of  the  styloid  process 
of  the  radium  for  a  distance  of  4  cm.,  is  entirely 
occluded  by  a  firmly  attached  coagulum.  The  re- 
mainder of  the  radial  artery  and  the  brachial  and 
axillary  are  free. 

Thoracic  Cavity. — Pericardium  without  change. 
Heart:  large  as  the  fist;  musculature  pale  red; 
contracted.  Valves  and  endocardium  soft  with  a 
greenish  yellow  color.  Ascending  aorta  shows 
slight  fatty  degeneration  of  the  intima.  Several 
hemorrhagic  spots  beneath  the  endocardium. 

Left  Lung:  Agglutinated  with  easily  soluble 
adhesions;  everywhere  filled  with  air;  especially 
in  marginal  regions  where  it  is  inflated. 

Right  Lung:     Same  condition  as  left. 

Larynx  and  pharynx  without  change. 

—  24  — 


8 AL VAR8 AN     FATALITIES 

Abdominal  Cavity. — Peritoneum  smooth  and 
glistening. 

Spleen:  Slightly  enlarged;  surface  smooth; 
color  dark  red;  structure  distinct. 

Liver:  Of  natural  size;  capsule  smooth;  con- 
sistence normal;  color  bluish  red  with  large  yel- 
low areas. 

Left  Kidney:  Of  natural  size;  capsule  detach- 
able; surface  smooth;  color  grayish  red;  structure 
changed  through  tissue  proliferation;  cortex  in- 
creased. 

Right  Kidney:     Same  condition  as  in  left. 

Suprarenal  bodies,  pancreas  and  stomach  with- 
out change. 

Bowel:  In  first  part  of  the  jejunum  isolated 
mucous  hemorrhages;  color  of  the  feces  dark  gray- 
ish blue. 

Pelvic  organs  without  change. 

Head  and  Spinal  Column:  Brain  remains  in 
toto;  in  the  right  parietal  bone,  in  the  region  of 
the  parietal  convulsion,  is  a  defect  the  size  of 
a  dollar,  the  edges  are  smooth,  and  the  whole  is 
covered  with  dural  tissue.  Brain  is  adherent  at 
this  point  and  shows  defect  (the  size  of  a  chest- 
nut), has  yellowish  color.  Over  wound  is  a  skin 
scar. 

A  microscopic  examination  carried  out  by 
myself  reveals: 

Kidneys:  In  the  uriniferous  tubules  flat, 
granular  masses  (albumin),  hyaline  casts, 
vacuolar  state  of  the  epithelium  of  the  tubuli 
contorti.  Glomeruli  rather  richer  in  nuclei 
than  normally,  but  without  important  changes. 

Liver:  Moderately  rich  in  fat.  Large  drops 
of  fat  within  the  cells  with  well  colored 
nuclei.  No  necrosis.  Interstitial  prolifera- 
tion such  as  seen  in  a  drunkard's  liver. 

Spleen :  Congested ;  the  inner  lining  of  the 
artery  of  the  duct  here  and  there  inlaid  with 

—  25  — 


SALVARSAN     FATALITIES 

a  somewhat  homogenous  substance  (probably 
hyaline)  ;  beyond  this  no  changes. 

Bowel :  Leucocyte  infiltration  in  the  super- 
ficial layer  of  the  mucosa;  no  necrosis. 

In  the  left  radial  artery  fresh  thrombosis 
(blood  plates,  leucocytes,  erythrocytes,  no  or- 
ganization). 

Dr.  Bielschowsky  found  nothing  in  the  brain 
indicating  an  acute  inflammatory  process.  But 
there  was  found  an  old  fibrous  leptomeningitis 
which  was  most  pronounced  where  the  two 
hemispheres  met.  There  were  further  chronic 
changes  in  the  cells  of  the  lamina  pyramidalis 
and  chronic  fibrous  tissue  proliferation.  In 
general,  the  picture  was  that  of  chronic  al- 
coholism. As  always,  there  were  also  present 
a  few  acutely  changed  cells,  but  these  had  no 
bearing  on  the  diagnosis. 

There  cannot  be  the  slightest  doubt  but 
that  the  heavy  drinking  and  the  former  epilep- 
tic attacks  should  have  been  a  sufficient  notice 
of  the  possibility  of  chronic  cerebral  changes. 
A  further  cause  for  care  should  have  been 
the  drug  exanthem  following  the  first  in- 
jection as  well  as  the  indisposition  which 
lasted  for  days.  That  in  all  probability,  the 
injection  was  made  into  the  radial  artery  after 
recognition  of  the  clinical  picture  and  the  con- 
dition of  the  artery,  is,  to  say  the  least,  not 
without  significance. 

The  entire  clinical  picture  and  the  patho- 
logical findings  of  our  only  case  do  not  in- 
dicate arsenic  poisoning.  And  furthermore, 
the  majority  of  the  other  cases  which  have 
been  carefully  and  thoroughly  examined  give 
only  an  irregular  picture  of  the  usual  symp- 

—  26  — 


SALVARSAN     FATALITIES 

toms  of  arsenic  poisoning.  Most  authors  give 
special  prominence  to  this  in  their  discussions. 
For  example  Almkvist  and  Hedren  say:  "At 
autopsy  there  were  no  characteristic  pathologic 
changes  of  acute  arsenic  poisoning,  such  as 
bowel  paralysis,  fatty  degeneration  of  the  kid- 
neys, the  liver,  the  heart  muscle  and  the  in- 
tima  of  the  blood  vessels.  Furthermore,  there 
was  no  hemorrhage  in  the  different  organs 
such  as  occurs  in  acute  arsenic  poisoning,  ex- 
cept in  the  brain.  That  this  case  cannot  be 
considered  as  an  ordinary  poisoning  by  ar- 
senic as  a  result  of  the  dose  of  salvarsan  (0.6), 
is  clear  without  question." 

"Busse  and  Merian  take  the  opposite  view- 
point. Should,  however,  any  doubt  yet  exist, 
it  may  be  dissipated  through  study  of  the 
older  and  half-forgotten,  yet  helpful,  litera- 
ture on  the  organic  changes  of  arsenic  pois- 
oning. From  the  description  of  isolated  cases 
of  poisoning  as  well  as  from  experimental 
studies,  one  is  led  to  conclude  that  in  some  in- 
stances arsenic,  just  as  exactly  as  with  the 
new  preparations,  has  an  individual,  distinc- 
tive action,  and  that,  at  other  times,  it  gives 
rise  to  the  same  changes  which  are  observed 
in  the  modern  treatment  of  syphilis.  I  shall 
pass  over  the  quite  extraordinary,  varying 
action  of  arsenic  on  the  different  organs,  such 
as  the  stomach,  intestinal  tract,  liver,  kidneys, 
etc.,  for  I  wish  to  refer  here  only  to  the  sim- 
ilar, not  to  say  identical,  changes  in  the  cen- 
tral nervous  system  produced  by  acute  and 
chronic  arsenic  poisoning  which  may  be  ob- 
served, as  in  our  case.  The  multiple  hemor- 
rhages in  the  central  nervous  system,  particu- 

—  27  — 


SALVARSAN     FATALITIES 

larly  in  the  spinal  cord,  have  been  the  object 
of  various  investigations  (Popoff,  Kreyssig, 
Wolkow,  Silbermann,  Heinz,  et  a/.)  ;  they 
were  investigated  jointly  with  the  thrombotic 
obliteration  of  vessels,  whose  nature  and  man- 
ner of  formation  in  arsenic  poisoning  was 
quite  closely  studied  especially  by  Heinz,  and 
explained  by  the  appearance  of  thrombi 
(thrombi  of  blood  corpuscles  and  mixed 
thrombi).  "It  must  also  be  emphasized  that 
in  these  cases  of  arsenic  poisoning  inflamma- 
tory infiltrations  of  the  tissue  occur,  and,  in- 
deed, not  only  following  subcutaneous  injec- 
tions but,  on  the  contrary,  also  in  cases  where 
the  poison  reaches  the  tissues  through  oral 
administration." 

"From  this  it  appears  that  the  unwelcome, 
severe  and  at  times  even  fatal  collateral  ef- 
fects following  the  administration  of  salvarsan 
and  neosalvarsan,  are  to  be  accepted  as  toxic 
actions  of  the  introduced  drug,  and  so  it 
seems,  principally  of  its  arsenic  constituent." 

It  is  quite  past  understanding  how  the  au- 
thors can  find  sufficient  support  in  the  cited 
literature  to  sustain  their  position  that  in  ar- 
senic poisoning  "similar,  not  to  say  identical, 
changes  in  the  central  nervous  system  may  be 
observed,  as  in  our  case."  Let  one  search  the 
literature  as  he  will,  yet  nothing  can  be  found 
which  could  be  offered  as  a  parallel.  In  the 
Handbook  of  Experimental  Pharmacology  by 
Heinz  nothing  on  the  subject  is  to  be  found. 
In  his  Breslau  Habilitation  thesis  (1891)  he 
throws  light  on  the  occurrence  of  thrombi 
in  the  capillaries  as  well  as  larger  vessels  due 
to  arsenic  poisoning,  this  being  based  on 

—  28  — 


SALVARSAN     FATALITIES 

varied  experimental  work,  but  nowhere  does 
he  mention  human  pathology  and  certainly 
not  hemorrhagic  encephalitis.  Silberrriann's 
investigation  (Virchow's  Archiv.,  117,  p.  304), 
so  far  as  this  point  is  concerned,  contains  just 
as  little.  Wolkow  (Virchow's  Archiv.,  127, 
p.  477)  concerns  himself  with  an  investigation 
into  degenerative  and  progressive  liver 
changes.  Popoff  (Virchow's  Archiv.,  113,  p. 
385)  finally  tries  to  prove  in  his  dissertation 
that  acute  arsenic,  lead  and  mercury  poisoning 
can  produce  acute  myelitis,  a  point  that 
Kreyssig  opposes.  Popoff  cites  a  fatal  case 
of  arsenic  poisoning,  but  this  died  with  gastro- 
intestinal symptoms  and  heart  failure  (cf. 
below)  and  without  coma.  Hemorrhages  and 
plastic  exudates  were  found  in  the  spinal  cord 
of  this  case.  This  is  the  only  case  in  point 
which  can  be  brought  forward  in  substantia- 
tion of  these  claims,  and  even  it  offers  an  en- 
tirely different  clinical  picture  from  that  of  a 
salvarsan  fatality. 

In  sharp  contrast  to  this  is  to  be  mentioned 
that  the  acute  arsenical  poisoning  described 
in  the  literature  plays  no  role  whatever  as  re- 
gards hemorrhagic  encephalitis  (vide  litera- 
ture by  M.  B.  Schmidt,  Ziegler's  contributions, 
VII  supplement,  Laignel  Lwastine  and  Voisin, 
Archiv.  de  med.  exp.  et  d'anat,  path.,  1907, 
No.  1  and  Meyer  Frankfurt,  Zeitschnft  fur 
Pathologie,  No.  5,  1910).  Furthermore,  in 
Crete's  valuable  investigation,  conducted  under 
the  guidance  of  Pick  and  Stadelmann,  on 
the  pathological  anatomy  of  arsenical  poison- 
ing (Berlin,  1912),  the  condition  of  the  brain 

—  29  — 


SALVARSAX     FATALITIES 

is  described  in  an  entirely  different  manner; 
there  is  nothing  on  hemorrhagic  encephalitis. 

Now,  there  is  an  acute  arsenical  poisoning 
which  corresponds  to  the  picture  of  arsenical 
asphyxia.  Concerning  it,  Grote  says :  "These 
cases  which  proceed  to  a  promptly  fatal  ter- 
mination, this  occurring  even  within  ten  hours 
can  run  their  course  quite  entirely  without 
any  trouble  referable  to  the  intestinal  canal. 
Finally  the  picture  of  narcosis  predominates 
yet  the  convulsive  forms  are  also  observed. 
Taylor*  reports  a  case  of  this  character  which 
terminated  fatally  within  twenty  minutes.  This 
form  is  not  so  rare ;  Harvey**  was  able  to 
find  it  in  36  out  of  697  cases. 

Seidel  in  Maschka's  Handbook  of  Medical 
Jurisprudence,  No.  II,  p.  241,  says  concern- 
ing the  cerebral  form:  "The  picture  of  gas- 
troenteritis appears  in  the  background  with 
perhaps  distress  or  occasional  vomiting,  but 
nothing  else;  these  may  be  entirely  lacking; 
in  the  foreground  stands  the  extraordinary 
weakness  with  small  pulse,  cool  skin,  the  oc- 
casional dizziness,  pain  and  a  feeling  of  numb- 
ness in  the  extremities  preceding.  The  patient 
falls  into  a  deep  swoon,  after  recovery  from 
which  he  is  sleepless  and  finally  becomes  de- 
lirious. Thereafter  follows  a  deep  coma,  now 
and  then  light  convulsions  and  death  comes  in 
the  midst  of  general  paralysis  with  complete 
unconsciousness.  The  course  is  very  rapid. 
Death  may  ensue  as  quickly  as  six  or  eight 
hours,  and  occurs  at  least  in  the  course  of 
the  first  day." 

*Die  Gifte,  ubers.  von  Seydler,  1862. 
**Ind.  Med.  Gaz..  1876. 

—  30  — 


SALVAR8AN     FATALITIES 

Heinz  also  says  on  this  score  (Handbook 
of  Experimental  Pathology  and  Pharmacol- 
ogy, Nos.  1,  2,  p.  929)  :  "The  acutest'form 
of  arsenical  poisoning,  in  which  a  large  quan- 
tity of  arsenic  has  been  taken  at  one  time, 
corresponds  irregularly  to  the  customary 
'gastro-intestinal'  form,  showing,  principally, 
evidences  of  impairment  of  the  central  ner- 
vous system  and  weakness  of  the  heart — the 
paralytic  form.  The  last  form  (especially 
rare  in  human  beings)  begins  with  an  uneasy 
sensation  and  vomiting,  yet  these  signs  may 
be  entirely  lacking.  The  principal  features 
are  marked  weakness,  very  weak  pulse,  and 
decline  of  temperature;  the  memory  quickly 
wanes ;  gradually  come  delirium,  loss  of  con- 
sciousness and  then  coma  until  finally,  with- 
out any  special  sign,  death  ends  the  scene. 
Death  comes  quickly;  usually  within  a  few 
hours,  not  often  longer  than  ten." 

That  does  not  correspond  to  the  picture  of 
a  salvarsan  fatality.  Especially  in  the  cere- 
bral type  of  cases  there  is  a  latent  period 
lasting  for  hours  and  even  several  days ;  this 
does  not  correspond,  as  Fischer  has  emphasiz- 
ed, to  the  picture  of  an  acute  poisoning. 

The  question  has  occurred  to  me,  whether 
the  cerebral  symptoms  making  up  the  clinical 
picture  really  constitute  its  central  feature. 
In  view  of  the  fact  that  in  all  of  these  fatali- 
ties coma  appears  prominently  in  the  fore- 
ground, I  directed  my  efforts  at  an  investiga- 
tion of  the  uremic  phenomena.  A  prominent 
characteristic  of  uremia,  as  pointed  out  by  v. 
Noorden*  is  its  tendency  to  present  strange 

*Handbuch  der  Pathologic  des  Stoffwechsels,  Bd. 
I,  p.  1002.  —31  — 


8ALVAR8AN     FATALITIES 

and  unexpected  manifestations.  As  a  matter 
of  fact,  Prof.  Loeb  found  urea  in  the  spinal 
fluid  in  the  proportion  of  0.5  gram  to  the 
litre,  and  marked  increase  of  rest  nitrogen 
in  the  blood.  (0.0174  per  cent.,  Holweg  0.21 
per  cent,  iron,  total  nitrogen  1.454  per  cent.) 

If,  after  full  consideration,  we  give  this 
accumulation  of  nitrogenous  products  its  most 
complete  significance,  we  cannot,  in  view  of 
Holweg's  investigations,*  consider  it  as  ab- 
solutely indicative  of  uremia,  but  it  is,  how- 
ever, certainly  an  expression  of  kidney  insuf- 
ficiency. This  opinion  conforms  also  to  the 
quantitative  investigations  made  by  Mestre- 
zat,**  who  found  in  suspension  of  the  renal 
function  without  uremia  0.25  to  1,  in  non- 
fatal  uremia  0.98  to  2.55,  in  fatal  uremia  3 
to  6.34  grams  of  urea. 

According  to  its  urea-content  our  case  be- 
longs to  the  first  group. 

Insufficiency  of  the  kidney,  therefore,  and 
not  hyper  sensitiveness  of  the  brain,  is  the  point 
of  the  entire  question  of  salvarsan  fatalities. 

It  thus  becomes  evident,  as  a  matter  of  fact, 
that  in  intravenous  injections  of  salvarsan  the 
overburdened  organ  is  the  kidney  and  not  the 
brain. 

The  largest  quantity  of  salvarsan  disappears 
rather  quickly  from  the  blood,  for  injected 
salt  solutions  do  not  remain  in  the  vessels. 

*Ueber  das  Verhalten  des  Reststickstoffs  des 
Blutes  bei  Nephritis  und  Uraemie.  Archiv.  f.  klin. 
Med.,  104  Bd.,  3-4.  Bei  der  Uraemie  erreicht  sie 
sehr  hohe  Grade  nach  Strauss  (Reststickstoff  in 
semen  Beziehungen  zur  Uraemie).  Ebenda,  Bd. 
106. 

**Le  liguide  ccphalo-rachidienne,  p.  592. 

oo 

—  •)-  — 


SALVAR8AN     FATALITIES 

The  blood  is  not  subjected  to  elimination  be- 
cause it  contains  no  free  water,  on  the.  con- 
trary all  water  is  associated  as  hydration- 
water  with  the  colloid  which  is  here  present. 
Conversely,  a  salt  solution  disappears  quickly 
from  the  circulatory  system  because  it  con- 
tains free  water.*  It  has  been  shown  by  Say- 
nisch**  that  oftentimes  in  so  short  a  space  as 
an  hour  after  the  injection,  arsenic  could  no 
longer  be  demonstrated  in  the  blood,  a  point 
which  control  experiments  have  further  con- 
firmed. Abelinf  found  the  salvarsan  reaction 
of  the  blood  after  one  hour  to  be  very  weak ; 
after  an  hour  and  a  half  still  less  certain  and 
after  two  hours  and  a  quarter  scarcely  ap- 
preciable. Yet,  as  regards  this  point,  it  must 
be  remembered  that,  as  Prof.  Loeb  has  shown 
me,  there  are  marked  individual  variations. 

After  intravenous  introduction,  salvarsan,  in 
largest  measure,  is  eliminated  through  the  kid- 
neys. 

It  is  a  well  known  fact  that  the  kidneys  al- 
ways tend  to  free  themselves  from  foreign 
substances  as  quickly  as  possible,  and  possess 
much  less  tolerance  to  such  than  to  the  physi- 
ological urinary  constituents.  Also  imme- 
diately, or  at  least  in  a  few  minutes  after  the 
injection,  one  may,  by  means  of  Abelin's  test, 
demonstrate  salvarsan  in  the  urine, ff  and,  gen- 

*Hoga  and  Martin  H.  Fischer.  Theorie  und 
Praxis  der  Transfusion  in  Ostwald,  Kolloidal- 
chemische  Beihefte,  III,  10-11. 

**Deutsche  Med.  Wochenschr.,  1912,  No.  44,  p. 
2070. 

iMuenchner  med.  Wochenschr.,  1912,  No.  2,  p. 
81. 

ttA&eHn.  Abhandlungen  uber  Salvarsan,  Bd.  II, 
p.  61. 

—  33  — 


SAL VAR8AN     FATALITIES 

erally  speaking,  its  entire  elimination  is  ac- 
complished in  five  or  six  hours.  As  a  rule, 
the  kidneys  easily  take  care  of  this  extra  bur- 
den, and  through  careful  examination  albumin 
is  rarely  found.  Schlasberg*  who  quite  re- 
cently has  thoroughly  investigated  these  cir- 
cumstances mentions  the  same  fact;  he  fre- 
quently found,  however,  occasional  hyaline 
casts.  We,  too,  have  had  urinary  examina- 
tions made  in  80  cases  after  intravenous  in- 
jections but  without  being  able  to  demonstrate 
hyaline  casts.  In  isolated  instances,  however, 
we  have  discovered  albumin ;  Weiler  reports 
the  same  condition.  While  it  is  a  very  rare 
occurrence,  yet  our  work  confirms  Weiler's 
observations.  Apparently,  in  these  cases  the 
question  is,  whether  the  affected  patients  did 
not  have  at  a  previous  time  a  kidney  lesion 
which  progressed  undiscovered  until  the  in- 
jection and  subsequent  urinary  examination. 
Now  comes  the  question :  How  does  an  al- 
tered kidney,  especially  a  luetic  kidney,  func- 
tion during  the  elimination  of  salvarsan  ?  We 
know  that  nephritis  occurs  during  the  pre- 
roseolous  stage  of  syphilis  but  more  especially 
during  the  secondary  period.  In  general,  the 
syphilitic  kidney  bears  salvarsan  well ;  we 
even  have  reports  of  improvement  and  cure 
of  syphilitic  nephritis,  and  this,  too,  in  instan- 
ces where  mercury  has  failed.  But  this  result 
is  not  without  its  exceptions.  Thus  Mariot** 
reports  in  a  presentation  on  the  action  of  ar- 

*Gesammelte  Abhandlungen  tiber  Salvarsan,  Bd. 
II.  p.  387. 

**Les  nephritis  de  syphilitiques  et  V  Arsenoben- 
zol.     Thtse.  Lille.  1912. 

—  34  — 


SALVARSAN     FATALITIES 

senobenzol  in  regard  to  syphilitic  nephritis, 
two  cases  that  died  in  uremic  states.  • 

As  a  rule,  however,  salvarsan  is  excellently 
borne  in  the  presence  of  nephritis  and  only 
exceptionally  are  bad  results  registered.  There- 
fore, there  apparently  is  offered  the  contra- 
diction that  plainly  pathological  kidneys  stand 
the  full  burden  of  salvarsan  without  reaction, 
while  on  the  other  hand,  seemingly  normal 
kidneys  are  rendered  insufficient.  The  judg- 
ment of  such  cases  in  no  way  depends  upon 
the  pathological  state  which  is  ascertained  to 
be  present;  a  nephritis  may  cause  death  with- 
out offering  an  anatomical  picture  even  ap- 
proximately .  in  keeping  with  the  severity  of 
the  clinical  manifestations  of  the  disease. 
Through  the  labors  of  Schlayer*  it  has  been 
shown  that  the  anatomical  investigation  of  the 
organs  does  not  always  disclose  as  much  dam- 
age of  the  renal  arterial  system  as  clinical  find- 
ings would  indiate  is  present.  Notwithstand- 
ing the  most  careful  studies  of  the  glomeruli, 
particularly  in  acute  nephritis,  we  have,  in  no 
sense,  progressed  so  far  as  to  be  able  to  de- 
termine positively  the  state  of  their  function 
from  the  anatomical  picture  presented  in  such 
cases.  Schlayer  and  Heubner  have  shown  that 
patients  with  a  severe  glomerulonephritis  may 
offer  only  the  most  insignificant  glomerular 
changes. 

We  encounter  with  extraordinary  frequency 
in  the  literature  on  salvarsan  fatalities,  in- 
stances of  death  occurring  with  anuria  or 
suddenly  appearing  albumin.  In  many  cases 

*ErgeT)nisse  tier  inneren  Medizin,  No.  2,  p.  576. 
—  35  — 


8ALVAR8AN     FATALITIES 

little  or  no  attention  whatever  has  been  paid  to 
the  urinary  function.  By  chance  one  may  note 
that  the  patient  has  fallen  into  this  condition, 
accidentally  discovering  that  but  a  small  quan- 
tity of  urine  is  being  eliminated. 

Let  me  cite  a  few  examples  of  this  class: 

Tucker's  Case.  (The  Therapeutic  Gazette,  No. 
9.  1911). 

Patient  well  developed,  muscular,  30  years  old. 
Three  weeks  before  chancre  appeared  on  prepuce. 
Has  always  been  healthy.  Heredity  without  in- 
terest. The  clinical  examination  disclosed  nothing 
abnormal  in  heart  or  lungs.  A  trace  of  albumin, 
however,  in  urine.  Skin  pale,  hot  and  damp.  Ex- 
tirpation of  right  inguinal  glands  (adenitis)  on 
April  29th.  On  May  5th,  a  maculo-papular  erup- 
tion broke  out  on  trunk  and  limbs.  Patient  com- 
plained of  pains  in  joints.  A  few  leucocytes  in 
urine.  Wassermann,  +  +  +.  At  half  past  two  in 
the  afternoon  of  May  12th,  patient  received  an 
injection  of  0.6  of  salvarsan.  In  one  hour  the 
injection  was  followed  by  nausea,  chills,  vomiting 
and  diarrhea.  Temperature  rose  to  39  (102.2 
Fahr.),  pulse  126.  In  the  morning  patient  felt 
quite  well,  no  more  diarrhea  but  since  the  time 
of  injection  has  not  urinated.  The  bladder  upon 
catheterization  found  to  be  empty.  Forty-eight 
hours  after  the  injection  the  condition  of  patient 
grew  worse,  the  cord-like  pulse  slowed  down  and 
symptoms  of  dyspenea  appeared.  Death  took  place 
two  and  one  half  days  after  injection  with  pa- 
tient entirely  conscious.  No  autopsy. 

Luque  Morata's  case  (Revista  de  Medicinia  y 
Cinejica  Practicas,  Feb.  28.  1911). 

Student  21  years  old.  Infected  two  years  be- 
fore. Treated  for  one  year  with  injections  of  grey 
oil.  Mucus  patches  in  mouth  and  pharynx.  Pa- 
tient very  emaciated,  weight  but  91  pounds.  No 
albuminuria,  heart  and  lungs  without  findings  of 
interest.  On  January  31st,  received  injection  of 
0.4  of  salvarsan  in  200  c.c.  0.9  per  cent  physio- 
logical salt  solution,  alkaline.  Three  hours  later 

—  36  — 


SALVARSAN     FATALITIES 


a  feeling  of  distress,  diarrhea,  profuse  perspira- 
tion. Soon  vomiting  of  a  green  color,  mixed  with 
blood.  Pale  lips,  dry  tongue,  pallid  face,  tempera- 
ture 36  (96.8  Fahr.),  scarcely  perceptible  pulse. 
Complete  anuria.  With  catheter  no  urine  secured 
from  bladder.  Delirium,  coma,  death  three  days 
after  injection.  No  autopsy. 

Caussade  and  Regnard's  case  (Bull,  de  la  Soc. 
m£d.  des  Hdpitaux,  February  20th,  1911). 

Patient  33  years  old.  Hard  chancre.  Later 
roseola  and  mucus  patches.  Mercury  very  badly 
borne  for  which  reason  patient  was  irregularly 
treated.  Then  considerable  edema;  albuminuria, 
5  grams  to  the  liter.  As  a  result  of  milk  diet 
declination  of  the  edema;  increase  of  albumin  to 
9  in  1,000.  Patient  very  weak,  emaciated,  bed- 
ridden. Small  urinary  excretion — 450  or  500  grams 
a  day.  Notwithstanding  mercurial  injections,  the 
oliguria  continued.  On  January  6th,  patient  was 
given  0.3  of  salvarsan  intravenously.  Well  borne. 
However,  the  oliguria  increased.  On  January  9th, 
the  amount  of  urine  excreted  was  but  50  grams; 
the  percentage  of  albumin  increased  to  33  grms 
per  liter.  On  the  eighth  day  of  anuria,  patient 
died  in  a  condition  of  cachexia  but  without  pain. 

Autopsy:  Acute  diffuse  nephritis  with  granular 
epithelial  and  amyloid  degeneration  of  the  glom- 
eruli. 

If  the  anuria  passes,  then  recovery  takes  place, 
as  illustrated  by  the  following  case. 

George  Livermore's  case.  Anuria  after  salvar- 
san (J.  A.  M.  A.,  1912,  October  5th). 

In  May,  1911,  a  nineteen-year-old  patient  de- 
veloped a  hard  chancre,  and  a  month  or  so  later 
secondaries  appeared.  For  six  months  he  was 
treated  with  mercury,  as  a  result  of  which  all 
manifestations  disappeared.  The  internal  organs, 
especially  the  kidneys,  sound.  On  July  2nd,  the 
patient,  who  showed  no  signs  of  lues,  was  given  an 
intravenous  injection  of  0.55  salvarsan.  In  one 
hour  vomiting  and  diarrhea  developed,  and  after 
a  time  anuria  became  evident.  On  the  next  day 
a  small  quantity  of  urine  was  drawn  off.  This 
urine  contained  much  albumin.  In  a  sLort  time 

—  37  — 


SALVARSAN     FATALITIES 


bfi 
E 


M 

£ 


—  38  — 


8ALVARSAN     FATALITIES 

the  uremic  symptoms  moderated,  after  which  full 
urinary  excretion  became  established. 

A  similar  case  is  also  reported  by  Wolff 
and  Mulzer.* 

A  seamstress,  27  years  old,  received  on 
June  1st,  1912,  0.7  neosalvarsan  intravenously, 
and  1.2  of  the  same  on  June  4th,  all  of  which 
was  borne  without  reaction.  On  June  8th, 
1.4.  On  the  following  day  temperature  was 
normal,  but  patient  suffered  from  severe  vom- 
iting. This  continued  until  the  15th.  On  June 
13th  complete  anuria.  Signs  of  interference 
with  function  of  lower  limbs.  June  17th,  se- 
vere cystitis,  albumin,  casts.  June  19th, 
marked  hemorrhagic  nephritis ;  anuria ;  bed- 
ridden. July  2nd,  anuria.  Extremely  small 
quantity  of  urine,  free  from  blood.  July  17th, 
condition  the  same,  albumin  and  casts. 

When  we  come  to  inquire  why  such  a  renal 
insufficiency  should  supervene,  why  an  occa- 
sional patient  of  the  thousands  injected  (I 
have  given  more  than  25,000  injections), 
should  suffer  this  fate,  I  am  convinced,  at 
least  so  far  as  my  patient  is  concerned,  that 
it  is  not  to  salvarsan  but,  on  the  contrary, 
to  the  combined  treatment,  mercury  and  sal- 
varsan, the  disaster  should  be  attributed.  In 
my  case  mercurial  treatment  was  carried  on 
for  two  weeks  under  my  supervision. 

Physicians  have  argued  with  much  warmth 
as  to  who  was  the  first  to  have  the  idea  of 
the  combined  treatment.  Indeed,  there  is 
scarcely  a  syphilologist  who  has  not  made  a 

*Muenchner  Med.  Wochenschr.,  1912,  No.  31. 
—  39  — 


8ALVARSAN     FATALITIES 

claim  for  priority  in  this  matter.  It  cannot 
at  all  be  questioned  but  that  the  combined 
treatment  has  certain  advantages,  and  occa- 
sionally I  have  myself  employed  it,  but  looking 
at  the  matter  with  scientific  eyes  one  cannot 
reach  a  definite  conclusion  as  to  the  difference 
between  the  action  of  mercury  and  salvarsan, 
nor  can  one  advance  unassailable  reasons  for 
the  use  of  mercury  in  one  case  and  salvarsan 
in  another,  any  more  than  he  can  say  when 
the  both  should  be  employed.  But  still  more 
regrettable  is  the  fact  that  no  one  has  yet 
answered  the  question:  What  harm  can  be 
produced  through  the  use  of  this  combination 
of  two  different  substances? 

It  is  quite  inconceivable  how  we  are  going 
to  determine  the  toxic  or  idiosyncratic  action 
of  salvarsan  if  we  combine  with  it  a  drug  such 
as  quicksilver,  which  can  cause,  even  in  the 
smallest  dosage  and  in  the  most  mysterious 
fashion,  varied  and  severe  collateral  effects 
and  even,  at  times,  a  fatal  termination.  Just 
today,  December  12th,  1912,  I  have  received 
into  my  department  a  woman  who  from  Oc- 
tober 5th  on  rubbed  her  husband  five  times 
with  mercurial  ointment,  and  who  now  suffers 
from  a  severe  necrotic  stomatitis,  than  which, 
notwithstanding  my  wide  experience  in  this 
field,  I  have  never  seen  a  worse  one. 

Particularly  so  far  as  it  relates  to  the  kid- 
neys this  observation  is  of  the  highest  import- 
ance. It  is  now  well  known  that  mercury  in 
a  large  percentage  of  cases  causes  an  irrita- 
tion of  the  kidneys  which  becomes  obvious 

—  40  — 


8ALVAR8A N     FATALITIES 

through  albuminuria  and  cylindruria.  Reiss* 
has  lately  pointed  out  the  extraordinary  fre- 
quency of  this  phenomenon.  By  reason  of 
the  disproportionate  excretion  of  the  mercury, 
this  condition  may  reach  at  times,  especially 
during  the  second  week  of  the  treatment,  a 
very  severe  grade. 

Salvarsan  irritates  the  kidneys  but  little,  es- 
pecially on  account  of  the  aromatic  character 
of  the  arsenic  combination.  Atoxyl  causes 
much  more  renal  irritation ;  arsacetin  produced 
according  to  Spiethoff**  a  constant  and  often 
times  a  lasting  irritation  of  the  kidneys  (al- 
bumin, hyaline  and  granular  casts)  a  point 
other  investigators  of  the  drug  (Neisser, 
Milian,  Lambkin  and  Salmon)  do  not  call  at- 
tention to.  Although  of  the  two  employed  in 
the  combined  treatment,  as  far  as  the  kidneys 
are  concerned  quicksilver  is  by  far  the  most 
pernicious,  yet,  however,  in  view  of  all  the 
circumstances  salvarsan  must  not  be  held  to 
be  entirely  innocuous. 

If  one  would  acquire  an  understanding  of 
the  circumstances  operating  in  this  matter, 
then  one  must  quit  thinking  of  the  postmortem 
kidney  which  the  pathological  anatomist  shows 
us  to  be  more  or  less  changed,  but,  on  the 
contrary,  one  must  make  use  of  the  living  kid- 
ney functioning  under  physiological  and  patho- 
logical conditions.  On  this  question  the  classic 

*Beitrag  zur  Kenntnis  der  bei  QuecTcsilberbe- 
Jiandlung  vorkommenden  Cvlindrurie.  Archiv.  f. 
Dermatol.,  Bd.  Ill,  2  Heft. 

**Compare  Borcher's  dissertation:  Die  toxischen 
NebenwirJcungen  des  Arsacetins  mit  besonderer 
Berucksichtigung  der  Nierenreizungen.,  Jena,  1910. 

—  41  — 


SALVARSAN     FATALITIES 

experimental  work  of  Schlayer*  and  his  co- 
workers,  on  the  toxic  nephritides  and  the  func- 
tion of  diseased  kidneys,  casts  a  welcome  beam 
of  light.  This  work  has  established  that  there 
is  a  fundamental  difference  between  the  ac- 
tion of  mercury  and  arsenic  on  the  kidney; 
the  two  drugs  act  upon  entirely  different  parts 
of  the  renal  tissue.  It  has  been  proven  with 
exactness  that  mercury  belongs  to  that  group 
of  substances  which  produce  a  pronounced 
tubular  nephritis ;  of  these  chromium  may  be 
accepted  as  the  type.  Therefore,  in  the  be- 
ginning there  is  a  good  secretion  with  com- 
pletely normal  function  of  the  vessels,  not- 
withstanding free  excretion  of  albumin  and 
the  presence  of  Targe  numbers  of  casts  with 
which  the  already  extensive  and  fixed  defects 
of  the  epithelia  well  coincide.  After  a  rather 
lengthy  existence  of  the  nephritis  there  grad- 
ually comes  a  diminution  in  the  capacity  of  the 
renal  vessels  to  dilate  and  with  it  a  decrease 
in  diuresis.  In  sharp  contrast  to  the  above 
there  is  the  other  group  of  toxic  nephritides, 
such  as  those  produced  by  arsenic  or  cantha- 
rides ;  these  cause  a  vascular  nephritis.  In 
this  group  there  occurs,  even  after  minimum 
doses,  a  marked  impairment  of  the  renal  ves- 
sels' power  to  dilate  as  well  as  to  contract, 
with  accompanying  suppression.  In  these 
cases  the  clinical  picture  offers  fewer  charac- 
teristics than  that  of  chromium  and  mercury 
poisoning;  furthermore,  the  quantity  of  albu- 


*  Schlayer  and  Hedinger.     Archiv.  f.  Tclln.  Medi- 
zin.,  Bi.  90-91. 

Schlayer  and  Takayasu,  ebenda  Bd.  98. 

—  42  — 


8ALVA R8 AN     FATALITIES 

min  as  well  as  of  casts  is  for  a  long  time  not 
so  large.  It  is  arsenic  particularly  which  al- 
ways affects  the  capillaries,  characterized,  es- 
pecially after  intravenous  injection,  in  a  short 
space  of  time  by  a  severe  impairment  of  the 
renal  function  even  increasing  in  severity  to 
the  extreme  of  complete  renal  insufficiency. 
In  connection  with  this  clinical  picture  there 
is  but  a  slight  anatomical  change. 

Toward  the  better  understanding  of  these 
fundamental  facto'rs,  let  me  quote  several 
tests  made  by  Schlayer  and  Hedinger  during 
the  course  of  their  "Experimental  studies  on' 
toxic  nephritis"  (/.  c.}.  In  these  studies  the 
renal  volume  was  secured  with  an  oncometer 
(Runne- Heidelberg),  and  the  blood  pressure 
in  the  carotid  recorded  with  a  special  instru- 
ment. By  means  of  an  electric  drop  counter 
devised  by  Prof.  Lowi  of  Vienna,  the  urinary 
excretion  from  both  kidneys  was  accurately 
gauged.  With  normal  animals  the  following 
results  were  gotten: 

After  the  kidney  volume  had  been  deter- 
mined by  means  of  an  accurate  level,  an  ap- 
preciable stimulation  was  employed,  whereupon 
occurred  a  quickly  transitory  rise  of  blood 
pressure  with  a  quick  drop  in  kidney  volume 
corresponding  to  the  contraction  of  the 
splanchnic  vessels.  Then  the  kidney  again 
quickly  dilated  with  an  approximate  return 
to  its  original  volume. 

Then  under  an  injection  of  adrenalin  (1 
drop  of  1  per  cent,  solution  in  0.5  c.c.  0.9  per 
cent,  salt  solution)  the  kidney  volume  showed 
a  marked  drop  with  enormous  rise  in  blood 
pressure.  After  return  to  a  normal  height,  5 

—  43  — 


8ALVAR8AN     FATALITIES 

per  cent,  sodium  chloride  solution  (5  c.c.  to 
the  kilogram)  was  injected.  This  caused  di- 
latation of  the  renal  blood  vessels  with  strong 
pulsation,  and  also  an  immediate  diuresis. 
After  cessation  of  the  dilatation  and  wane  of 
the  diuresis,  caffeine  (2  c.c.  5  per  cent,  solu- 
tion pro  \]/2  kg.)  was  injected,  whereupon 
occurred  the  same  phenomena,  viz.,  dilatation 
of  the  renal  vessels  and  diuresis.  Finally,  fre- 
quent injections  of  phloridzin  were  given  which 
in  normal  animals  caused  moderate  diuresis 
with  glycosuria  but  without  increase  in  kid- 
ney volume. 

The  phenomena  attending  chromium  pois- 
oning are  shown  by  the  following  experiment 
and  curve: 

Rabbit  No.  19,  weight  1,500  grams,  received  1 
c.c.  chrom.  potassium  (2.00 — 15.00)  subcutaneously. 
No  diarrhea.  The  animal  is  visibly  sick.  Bladder 
half  full.  Urine:  enormous  quantity  of  casts,  es- 
pecially granular  and  epithelial,  a  few  erythro- 
cytes;  albumin  about  6  per  cent.  (Esbach). 

Upon  appreciable  stimulation  fairly  well  marked 
contraction  sets  in;  with  adrenalin*  somewhat 
less.  With  chloride  of  sodium  minimum  dilatation 
of  the  kidney  but  however,  without  diuresis,  al- 
though the  ureters,  as  shown  by  tests,  are  per- 
meable. With  caffeine  is  noted  a  retarded  and 
very  slight  dilatation  with  minimum  secretion. 

Pathological  anatomy:  Kidney  large;  medul- 
lary substance  moderately  hyperemic;  cortex  pale. 

Microscopical:     Almost  complete  necrosis  of  the 


*During  this  contraction-reflex  the  secretion  was 
incorrectly  gauged.  This  was  caused  by  the  es- 
cape of  the  salt  solution  with  which  the  bladder 
was  filled,  a  consequence  of  contraction  of  the 
bladder  and  ureters  due  to  the  adrenalin.  This 
occurred  a  number  of  times  in  the  beginning  of 
this  work. 

—  44  — 


S ALVARS AN     FATALITIES 


entire  cortex,  only  at  occasional  sites  a  few  re- 
maining tubules,  casts  in  lumen  plentiful.  Glom- 
eruli  large,  showing  irregular  swelling  of  the'  cap- 
sule. Suggestion  of  albumin-ring  in  the  fine  net- 
work between  capsule  and  glomeruli. 

These  phenomena  are  associated  with  sublimate 
poisoning: 

Rabbit  No.  11,  weight  1,300  grams,  received  sub- 
cutaneously  21/£  c.c.  of  a  1  per  cent,  solution  of 
sublimate  71  hours  before.  The  animal  is  yet 
quite  lively,  has  no  diarrhea.  The  bladder  is  half 
full;  the  urine  contains  hyaline  and  granular 
casts  and  epithelium  in  plenty,  but  very  few  ery- 
throcytes.  Albumen  about  5  per  cent. 

Pathological  anatomy:  Kidney  rather  large, 
cortex  pale. 

Microscopical:  Large  quantity  of  casts  in  the 
tubules  of  the  medulla,  variously  also  in  the  cor- 
tex. Large  quantity  of  a  spotted,  flaky  disinte- 
grated substance  (lime  deposits)  in  the  epithelium 
of  the  convoluted  tubules;  likewise  in  the  ascend- 
ing loops;  many  of  the  tubules  are  entirely  de- 
nuded of  epithelium. 

The  glomeruli  show  a  scarcity  of  nuclei,  mod- 
erately congested,  do  not  fill  out  the  capsule  en- 
tirely. Nowhere  is  there  any  exudate. 

Finally,  toward  the  end,  with  large  doses 
and  after  three  or  four  days'  duration  the 
following  functional  phenomena  exhibited 
themselves : 

Upon  appreciable  stimulation  and  adrenalin 
contraction  of  the  kidney  still  occurred,  upon 
which  diuretics  scarcely  produced  any  im- 
pression. The  diuresis  itself  is  very  slight. 
Neither  diuresis  nor  glycosuria  followed 
phloridzin.  The  bladder  is  still  rather  well 
distended.  The  urine  contains  many  casts  of 
all  sorts,  and  epithelium.  Erythrocytes  not 
plentiful.  Albumin  in  large  amount. 

The  pathological  findings  in  this  stage  reveal 

—  45  — 


SALVARSAN     FATALITIES 


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—  46  — 


SALVARSAN     FATALITIES 

marked  necrosis  of  the  epithelium  in  the  in- 
jured tubules  and  in  the  pyramids,  particularly 
in  the  ascending  limbs  of  the  loops.  In  the 
glomeruli  there  are  now  no  marked  changes, 
only  occasional  epithelial  swellings  in  the  cap- 
sule, no  definite  exudates,  none  or  only  an  oc- 
casional desquamation  of  the  capsule  epithe- 
lium. 

This  stage  is  illustrated  by  the  following: 

Rabbit  No.  9,  weight  1,550  grams,  received  84 
hours  before  0.8  c.c.  of  a  1  per  cent,  solution  of 
sublimate  under  the  skin,  then  60  and  36  hours 
before  respectively,  1%  c.c.  of  the  same  solution. 
The  animal  is  somewhat  weak.  Has  no  diarrhea. 
The  bladder  is  full.  The  urine  contains  large 
quantities  of  casts,  principally  granular,  moderate- 
ly numerous  epithelial  cells  and  erythrocytes.  Al- 
bumin 4  per  cent. 

Pathological  anatomy:  The  kidney  is  very  large, 
the  cortex  pale  and  shows  fine  radiating  stripes. 

Microscopical:  Many  casts  in  the  excretory 
canals,  also  in  the  convoluted  tubules  of  the  laby- 
rinth and  cortex.  Occasional  hemorrhages  in  the 
border  regions.  The  injured  uriniferous  tubules 
and  particularly  the  ascending  loops  exhibit  very 
wide  spread  flaky  necrosis  (lime  deposits),  the  still 
remaining  epithelium  shows  mostly  poor  nuclear 
staining  and  cloudy  protoplasm.  Many  tubules 
for  long  distances  are  denuded  of  epithelium.  The 
glomeruli  are  hemorrhagic,  rather  poor  in  nuclei, 
entirely  fill  the  capsules;  only  here  and  there  can 
one  find  a  suggestion  of  swelling  of  the  capsule 
epithelium. 

We  see,  therefore,  that  sublimate  nephritis 
in  its  functional  course  offers  exactly  the  same 
picture  as  chromium  nephritis ;  in  the  begin- 
ning there  is  good  secretion  with  completely 
normal  function  of  the  vessels  notwithstand- 
ing an  abundant  excretion  of  albumin  and  the 

—  47  — 


8ALVAR8 AN     FATALITIES 


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—  48  — 


8ALVARSAN     FATALITIES 

presence  of  many  casts  with  which  the  already 
extensive  anatomical  damage  of  the  epithelium 
coincides. 

Only  after  a  lengthy  existence  of  the  ne- 
phritis and  after  high  dosage  of  the  causative 
agent,  there  occurs,  with  severe  damage  of  the 
tubules,  a  gradual  diminution  of  the  renal 
vessels'  capacity  to  dilate  and  a  decline  in 
diuresis,  which  both  finally  become  entirely 
nil. 

In  all  stages,  however,  the  contractility  of 
the  renal  vessels  remains  constant,  except  to- 
ward the  end  it  is  somewhat  less  than  normal. 

In  regard  to  the  functional  phenomena  it 
has  been  shown  that  the  polyuria  of  the  initial 
stage  is  not  so  marked  in  chromium  poisoning 
as  in  poisoning  by  other  drug,  and  further  the 
sublimate  nephritis  distinguishes  itself  from 
chromium  nephritis  in  two  ways  as  far  as  the 
pathological  anatomy  is  concerned :  The  one  is 
the  strikingly  slight  impairment  of  the  glom- 
eruli  as  shown  in  the  histological  picture ;  even 
with  almost  completely  suspended  capacity  of 
the  vessels  to  dilate,  epithelial  swelling  of  the 
capsule  is  found  at  only  a  few  points.  No- 
where is  there  exudate,  etc.  The  second  point 
of  difference  is  to  be  found  in  the  deposits  of 
lime  after  large  doses  continued  for  some 
time. 

We  shall  come  back  later  to  the  first  point. 
The  second  makes  it  clear  that  there  must  be 
a  difference  in  the  biochemical  course  between 
chromium  and  sublimate  poisoning,  but  it 
shows,  however,  at  the  same  time  that  not- 
withstanding this  difference  in  the  functional 

—  49  — 


SALVARSAN     FATALITIES 


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—  50  — 

SALVA RS AN     FATALITIES 

phenomena,  the  result  to  the  organism,  so  far 
as  investigated,  can  be  entirely  similar.*- 

But  entirely  different  are  the  conditions  at- 
taching to  cantharides,  which  point  is  illus- 
trated by  the  following : 

Rabbit  No.  7,  weight  1,500  grams,  four  and  one- 
half  hours  before  the  beginning  of  the  experi- 
ment, received  a  subcutaneous  injection  of  i/>  c.c. 
of  cantharidin,  1:100  or  0.005.  Animal  seems 
quite  lively.  The  bladder  contains  bloody  urine 
in  small  quantity.  In  the  urine  is  an  abundance 
of  epithelial  cells,  large  erythrocytes,  rather  plen- 
tiful epithelial  casts,  little  albumin  (about  1  per 
cent.)  in  filtered  urine.  Kidney  pulsates  fairly 
•well. 

Rabbit  No.  13,  weight  1,400  grams,  nine  and  one- 
half  hours  before  beginning  of  experiment  re- 
ceived a  subcutaneous  injection  of  %  c.c.  canthari- 
din, 1:100  or  0.005.  The  animal  has  diarrhea  and 
appears  weak.  The  bladder  is  nearly  empty.  In 

•Observation.  Our  investigations  show  that  the 
supposed  capillary  thrombosis  held  by  Kaufmann, 
Silbermann  and  others  to  be  the  cause  of  the  death 
of  the  epithelium,  is  not  necessarily  present  in 
sublimate  nephritis  in  rabbits  or,  at  least,  not  to 
any  great  degree.  We  see,  notwithstanding  ex- 
tensive and  severe  lesions  of  the  epithelium,  a 
marked  capacity  of  the  renal  vessels  to  dilate  and 
contract  as  well  as  prompt  reduction  of  kidney 
volume  following  the  opening  of  a  vein  to  produce 
death.  It  would  be  impossible  for  both  to  be 
present  with  any  extensive  capillary  thrombosis. 
Even  in  the  final  stages  the  kidney  still  has  good 
contractility,  and  its  pulsation  becomes  stronger 
after  the  use  of  diuretics,  so  that  also  in  this  stage 
no  marked  capillary  thrombosis  can  be  present,  as 
we  would  necessarily  have  to  accept  in  explana- 
tion of  the  enormous  destruction  of  the  epithelium 
according  to  the  explanation  given  by  Kaufmann. 
Our  results  in  this  respect  confirm  the  views  pro- 
mulgated by  Klemperer,  that  the  condition  is 
reached  in  some  other  manner. 

—  51  — 


SALVARSAN     FATALITIES 


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—  52  — 

8 ALVA RS AN     FATALITIES 

the  urine  are  numerous  swollen  epithelial  cells, 
few  casts,  many  erythrocytes.  Albumin  not 
definite.  Curve  4,  figure  III,  illustrates  the  course. 

Thus,  the  deleterious  effect  following  can- 
tharidin  is  entirely  different  from  that  of 
chromium  and  sublimate.  All  experimental 
work  shows  with  great  clearness  that  can- 
tharidin  has  a  totally  different  action  on  the 
kidneys  from  that  produced  by  chromium. 

After  the  shortest  time,  even  after  minimum 
doses,  there  occurred  an  enormous  impair- 
ment of  the  dilatability  as  well  as  contractility 
of  the  renal  vessels,  with  coincident  failure 
of  diuresis.  At  the  same  time  the  clinical  in- 
vestigation showed  much  fewer  phenomena 
than  with  chromium,  likewise  the  quantity  of 
casts  as  well  as  albumin  was  not  near  so  great ; 
the  striking  feature  was  the  abundance  of  ery- 
throcytes. 

With  longer  protracted  or  severer  poisonous 
influence  a  complete  insufficiency  of  the  renal 
vessels  develops,  the  pulsation  of  the  kidney 
and  urinary  excretion  cease  entirely,  but  the 
pathological  examination  does  not  disclose  a 
condition  that  corresponds  with  the  renal  dis- 
turbance such  as  one  may  find  in  the  less 
pronounced  impairment  of  the  urinary  func- 
tion following  chromium  poisoning. 

According  to  all  observations  in  regard  to 
cantharides  nephritis,  the  clinical  picture  Is 
that  of  a  marked,  very  rapidly  setting  in  dis- 
ease of  the  renal  vessels.  If  this  assumption 
be  correct,  then  it  remains  that  a  poison  which 
spends  its  force  mainly  in  the  capillaries,  will 
produce  the  same  sort  of  an  effect. 

—  53  — 


SALVAR8 A N     FATALITIES 

We  found  the  same  to  hold  good  in  regard 
to  arsenic.  Boehm*  and  Schmiedeberg** 
through  their  investigations  have  shown  this 
characteristic,  and  recently  it  was  demonstrat- 
ed through  the  efforts  of  Magnusf  who  pro- 
duced a  marked  edema  through  saline  infusion 
following  the  injection  of  arsenic.  He  also 
holds  the  opinion  that  arsenic  is  to  be  looked 
upon  as  a  typical  capillary  poison. 

In  our  experimental  work  we  subjected  ani- 
mals to  arsenic,  and  even  employed  arsenous 
acid  in  one  per  cent,  solution  intravenously  as 
well  as  subcutaneously.  In  all,  three  demon- 
strations were  made  in  this  manner.  Two  of 
them,  the  one  treated  with  an  intravenous  so- 
lution, the  other  with  subcutaneous,  are  cited 
here. 

Healthy  rabbit  of  1600  grams.  No  albumin  in 
urine.  Left  kidney  connected  with  oncometer. 

Pathologico-anatomical  findings.  Kidney  large, 
cortex  rather  markedly  hyperemic. 

Microscopical:  Occasional  hemorrhagic  spots, 
especially  in  the  border  strata.  But  a  few  casts 
in  the  excretory  canals.  The  epithelia  of  the 
tubuli  contort!  involved  to  a  slight  extent.  No-' 
where  damage  to  nuclei.  Staining  of  nuclei  good. 
No  fusion  of  the  protoplasm.  The  glomeruli  are 
very  much  congested  and  fill  their  .capsules  en- 
tirely. They  contain  nuclei  in  abundance.  With 
most  there  is  epithelial  swelling  of  the  capsule. 
With  some  desquamation  (?).  Nowhere  exudate. 

Rabbit,  weighing  1550  grams,  received  a  sub- 
cutaneous injection  of  1%  cc.  of  a  1%  sol.  arsen. 
acid,  seven  hours  before  beginning  of  experiment; 
four  hours  later  another  injection  (1  cc.)  of  the 


*Arch.  f.  exp.  Pathol.  u.  Pharm.  Bd.  2  and  16 
**Schmiedeberg,    Grundrisz   der  Pharmakol.   1 
Aufl.  p.  406.  ff. 

\.  f.  exp.  Path.  u.  Pharm.,  Bd.  42,  p.  267. 

—  54  — 


SALVARSAN     FATALITIES 

same.  The  bladder  is  empty.  The  animal  has 
diarrhea  and  is  somewhat  weak. 

Pathologico-anatomical  findings:  Kidney  is 
large,  the  border  regions  markedly  hyperemic. 

Microscopical:  Moderately  abundant  casts  in 
excretory  canals;  likewise  in  the  border  regions; 
only  moderately  abundant  hemorrhages.  The  epi- 
thelium of  the  tubuli  contorti  indicates  rather  ex- 
tensive cloudiness  of  the  protoplasm,  which  in  oc- 
casional tubules  is  coagulated  in  flakes.  At  the 
same  time  damage  to  the  nuclei  is  not  clearly  es- 
tablished. The  glomeruli  are  very  much  con- 
gested, and  fill  the  capsules  completely;  rather  rich 
in  nuclear  elements;  occasional  slight  desquama- 
tion  of  the  capsule,  as  a  rule  but  moderate  swell- 
ing, no  exudate. 

We  find  therefore,  as  was  expected  from  the 
above  mentioned  observations,  an  entirely 
analogous  behavior  of  the  renal  circulatory 
system  with  arsenic  as  with  cantharidin.  After 
a  short  period,  especially  with  intravenous  in- 
jection, serious  impairment  of  the  organ's 
power  to  dilate  as  well  as  to  contract  was 
noted,  with  complete  cessation  of  diuresis. 

Also  in  this  experiment,  there  appears  in 
its  final  stages  a  phenomenon  of  the  renal 
blood  supply  similar  to  that  attending  the  use 
of  cantharidin.  A  secondary  increase  in  vol- 
ume of  the  kidney  following  stimulation  of 
the  capacity  of  contraction.  Likewise,  as  with 
cantharidin,  the  secretion  of  urine  is  relatively 
less ;  there  are  rather  more  casts  and  a  smaller 
amount  of  albumen  with  complete  renal  in- 
sufficiency. The  pathological  findings  are  even 
less  than  with  cantharidin.  It  might  well  be 
that  more  marked  phenomena,  especially  of 
the  glomeruli,  would  appear  with  a  longer 
duration  of  the  nephritis;  for  us  the  essential 

—  55  — 


SALVARSAN     FATALITIES 


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—  56  — 


SALVARSAN     FATALITIES 

feature  was  the  determination  of  a  less  notice- 
ably marked  anatomical  change  with  well  prov- 
en renal  insufficiency. 

A  difference  between  arsenic  and  cantharidin 
is  to  be  found  in  the  blood  pressure,  which 
falls  very  much  faster  and  deeper  after  the 
first  than  following  the  use  of  the  latter  agent. 

In  seeking  a  reason  for  this  difference,  we 
find  it  could  be  caused  either  through  the  ac- 
tive influence  which,  as  is  well  known,  arsenic 
exerts  upon  the  vasomotor  center,  or  through 
the  wide  extension  of  the  damage  inflicted  upon 
the  peripheral  capillaries. 

Perhaps  one  cannot  entirely  accept  the  prop- 
osition that  salvarsan  in  the  abstract  has  the 
same  effect  as  arsenic  upon  the  renal  blood 
supply  but  it  acts  in  the  same  sense  as  the 
demonstrated  reduction  of  blood  pressure  (as 
shown  in  my  patients  by  Professors  Nikolai 
and  Siesskind)  proves,  especially  after  intra- 
venous introduction.  At  times  a  slight  impair- 
ment which  has  existed  may  become  changed 
into  a  fatal  danger,  especially  when  the  func- 
tion of  the  renal  circulatory  system  has  suffer- 
ed through  the  previous  administration  of  an- 
other poison. 

Practically  all  fatal  cases  of  salvarsan 
therapy  in  the  person  of  healthy,  strong  pa- 
tients, show  the  fatal  combination  of  energetic 
mercurial  treatment  and  the  intravenous  in- 
jection of  salvarsan. 

One  might  well  complain  that  salvarsan  fa- 
talities are  not  sufficiently  explained  by  the 
above  in  view  of  the  immense  number  of  re- 
corded cases  in  which  the  combined  treatment 
was  employed  without  any  evil  feature.  It 

—  57  — 


SALVARSAN     FATALITIES 

depends  wholly  upon  what  period  of  observa- 
tion an  investigation  of  the  burden  thrown  by 
salvarsan  upon  a  kidney  already  damaged  by 
mercury,  is  taken  up.  With  moderately  severe 
intoxication  with  sublimate,  it  is  seen  in  ex- 
periments, that  on  the  first  day  of  the  poison- 
ing, with  increased  intake  of  salt,  polyuria  oc- 
curs with  somewhat  augmented  excretion  of 
the  saline,  but  that  the  same  increase  of  intake 
on  the  second  and  following  days  is  responded 
to  by  a  marked  incapacity  to  eliminate  the 
saline.  The  excretion  of  iodide  of  potassium 
is  also  delayed.  The  excretion  of  milk  sugar 
from  the  beginning  and  thenceforth  proceeds 
well,  so  much  so  that  from  the  second  day  the 
excretory  curves  of  the  saline  and  the  sugar 
diverge  widely.  Only  on  the  fourth  day  as 
the  damage  to  the  capillaries  becomes  marked 
does  retardation  of  excretion  of  lactose  set  in. 
Therefore,  the  kidney  can  yet  eliminate  milk 
sugar  when  for  a  long  period  it  has  no  longer 
responded  to  an  increase  of  salt  intake.  In 
the  case  of  renal  congestion  caused  by  arsenic, 
the  animals,  in  most  instances,  die  quickly  in 
anuria.  Where  investigation  was  possible,  re- 
tardation of  lactose  excretion  manifested  it- 
self. It  is  not  fixed  as  to  which  type  the  sal- 
varsan excretion  belongs ;  however,  it  may  by 
reason  of  damage  done  by  mercury  to  the  kid- 
neys, undergo,  under  all  circumstances,  a  sub- 
stantial retardation.  Concerning  the  above,  one 
is  at  once  clear,  if  he  observes  the  circum- 
stances attending  mercurial  poisoning  in  cases 
which  do  not  terminate  fatally.  Thus,  for  ex- 

—  58  — 


8ALVARSAN     FATALITIES 

ample,  Pfeiffer*  reports  from  the  clinic  of 
Quincke,  a  case  of  a  young  man  who  had  taken 
a  teaspoonful  (  ?)  of  sublimate,  but  who  at 
once  drank  lukewarm  milk  and  vomited  freely. 
This  patient  recovered.  During  his  stay  in 
the  hospital  polyuria  took  place  on  the  first 
day,  followed  by  suppression  until  the  eighth 
day  at  which  time  polyuria  again  occurred. 
The  circumstances  are  shown  most  clearly  by 
the  following  record.  (See  Table  VIII.) 

Anuria  is  a  conspicuous  symptom  of  mer- 
curial poisoning.  Only  those  cases  in  which 
it  is  overcome,  end  favorably.  Thus  Kolb** 
reports  the  case  of  a  sister  and  brother  who 
took  bichloride  with  suicidal  intent.  The  sister 
died  with  total  suppression.  The  brother 
passed  eight  days  with  the  excretion  of 
but  31  c.c.  of  urine;  this  contained  hyaline, 
granular  and  epithelial  casts  and  white  and  red 
blood  cells.  There  was  an  immense  quantity 
of  albumin  for  six  days,  after  which  the  quan- 
tity diminished  so  that  on  the  twelfth  day  but 
a  slight  trace  was  found  with  acetic  acid-fer- 
rocyanide  of  potassium.  At  this  period  the 
excretion  of  urine  ran  up  to  3,500  c.c.,  then 
dropped  to  2,500-3,000  c.c.  (sp.  gr.  ranging 
from  1,002  to  1,012)  where  it  remained.  Upon 
admission  of  the  patients  blood  pressure  was 
normal ;  on  the  third  day  that  of  the  sister  280, 
that  of  the  brother  230.  According  to  Geis- 
bockf  the  blood  pressure  at  first  rises  and  then 
sinks  until  the  end  comes;  he  recorded  125, 

*Ueber  akute  Sublimat-  und  Oxalsdurevergift- 
ung.  Archiv  f.  klin.  Med.  Nr.  90,  S.  591. 

**Muench.  med.  Wochenschrift.     1904,  p.   582. 
iArchiv  f.  klin.  Med.    Vol.  83. 

—  59  — 


SALVA R8AN     FATALITIES 


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—  60  — 


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8ALVAR8AN     FATALITIES 

110,  80,  70,  60.  In  such  cases,  as  mentioned 
by  Hohlweg,*  notwithstanding  that  no  evi- 
dence of  uremic  symptoms  supervene,  there 
is  retention  of  nitrogenous  products.  He  re- 
ports two  cases  of  acute  mercurial  poisoning. 

"Regarding  the  first  patient  (a  female),  who 
was  received  into  the  hospital  24  hours  after 
taking  four  oxycyanate  pastilles  of  one  gram 
each,  there  was  complete  anuria  from  the  be- 
ginning of  the  period  of  observation  until 
seven  days  later  when  death  took  place.  Not 
one  drop  of  urine  was  secured  through  the  ca- 
theter when  introduced  into  the  bladder.  Mark- 
ed diarrhea  with  bloody  passages  occurred; 
edema  was  not  a  symptom.  The  blood  pres- 
sure oscillated  between  105  and  130  mm.  Hg. 
The  patient  died  without  any  uremic  manifes- 
tations. Autopsy  denied. 

"The  second  patient  (also  a  female)  on 
December  15th,  1910,  swallowed  half  of  a 
sublimate  pastille.  Nothwithstanding  the 
prompt  attendance  of  a  physician  who  em- 
ployed the  stomach  pump,  washing  out  the 
stomach,  there  occurred  on  the  following  day 
intense  abdominal  pain  and  watery  stools 
which,  however,  were  not  bloody.  On  Decem- 
ber 19th,  the  patient  was  sent  to  the  hospital. 
Up  to  this  time  patient  has  not  passed  any 
urine.  Upon  admission  into  hospital  patient 
was  apathetic  but  not  unconscious.  During 
her  second  day  in  the  hospital  patient  fre- 
quently vomited  grayish  green,  vile  smelling 
masses.  On  December  20th,  blood  pressure 
was  135  mm.  Hg.  On  the  same  day  by  means 
of  the  catheter  4  c.c.  of  urine  was  removed ; 

*l.  c.  p.  234. 

—  61  — 


SALVARSAN     FATALITIES 

this  contained  much  albumin,  many  leucocytes, 
hyaline  and  granular  casts.  On  December  21st 
15  c.c.  of  urine  secured.  On  the  same  day  at 
11  o'clock  a.  m.  venesection  was  employed;  12 
hours  later  death  took  place.  No  uremic  symp- 
toms had  set  in.  Autopsy  disclosed  eschars 
on  tongue  and  mucous  lining  of  cheeks,  striped 
hemorrhages  of  the  stomach  and  colon  mu- 
cosa.  There  was  about  200  c.c.  of  urine  in 
the  bladder.  The  kidneys  showed  extensive 
necrosis  of  the  epithelium  with  proliferation 
of  the  uriniferous  tubules  (Geh.  Rat.  Bos- 
troem). 

"In  the  first  case  venesection  was  performed 
54  hours  before  death,  in  the  second  case  12 
hours. 

"The  figures  for  the  total  rest-nitrogen  were 
respectively  0.204  and  0.298;  for  the  portion 
precipitated  with  tannin  0.000  and  0.015;  for 
the  portion  not  precipitated  through  tannin 
0.033  and  0.045 ;  for  urea  nitrogen  0.071  and 
0.238." 

This  enormous  retention  of  nitrogenous  pro- 
ducts of  the  blood  is  the  expression  of  the  in- 
capacity of  the  kidneys  to  remove  these  pro- 
ducts from  the  organism.  One  can  easily  un- 
derstand that  this  insufficiency  for  foreign  sub- 
stances, such  as  salvarsan,  must  be  of  a  still 
higher  grade  and  with  marked  oliguria  can  be 
fatal. 

There  may  happen  a  vascular  sensitiveness 
of  the  kidneys  expressing  itself  in  poly — and 
oliguria,  but  without  albuminuria,  in  many  pa- 
tients upon  the  administration  of  small  doses 
of  mercury.  There  is  even  a  number  of  re- 
corded deaths  from  minimum  doses  of  mer- 

—62  — 


8ALVARSAN     FATALITIES 

cury,  for  example,  from  a  small  quantity  of 
gray  ointment  applied  for  the  relief  of  pedicu- 
losis. Volk  reports  the  death  of  a  patient  who 
only  lay  in  the  same  room  with  other  patients 
who  wore  small  Welander  sacks.  It  was  a  21- 
year-old  patient  suffering  from  tuberculosis. 
In  the  room  in  question,  which  had  an  air  ca- 
pacity of  750  cubic  metres,  there  were  24  pa- 
tients of  whom  5  or  6  wore  the  sacks,  while 
with  the  others  the  application  of  mercury 
was  not  carried  on  in  this  room.  In  nine  days 
there  was  swelling  of  the  tongue  which,  not- 
withstanding the  most  careful  attention,  in- 
creased in  severity.  Although  thereafter  the 
patient  was  placed  in  a  room  practically  free 
from  mercurial  influence,  the  condition  pro- 
gressed to  ulcerative  stomatitis  which  contin- 
ued without  stop  until  death  came.  Mercury 
was  found  in  the  urine  and  kidneys  in  abund- 
ance.* Hitherto,  entirely  too  little  consid- 
eration has  been  paid  to  the  excretion  of  urine 
in  persons  manifesting  a  susceptibility  to  mer- 
cury. Thus,  just  lately  I  have  observed  a 
young  man  who  exhibited  indications  of  in- 
sufficiency of  the  pulmonary  valves,  this  mani- 
festing itself  in  weakness  of  ventricular  ac- 
tion, and  a  maximum  blood  pressure  of  105 
with  a  minimum  of  80.  On  account  of  a  re- 
curring angina  he  received  on  the  10th,  18th, 
21st  and  25th  of  September,  1912,  salvarsan, 
0.1  each  time.  As  with  each  injection  the  tem- 
perature rose  to  38  C.  (100.5  Fahr.),  with 
diarrhea  and  headache  of  a  moderate  degree, 
I  refrained  from  further  injections.  On  Oc- 


*Dermat.  ZeitscJirift,  Bd.  XV,  606. 
—  63  — 


SALVARSAN     FATALITIES 

tober  14th,  15th  and  16th,  the  patient  was  rub- 
bed with  ungt.  ciner.,  4  grammes  being  used 
each  time.  On  account  of  diarrhea  and  gen- 
eral discomfort  this  treatment  was  also  in- 
terrupted. Loss  of  appetite  continued.  In 
the  urine  there  was  no  albumin  or  sugar,  nor 
were  casts  present ;  the  quantity  of  urine  was 
950  c.c.  on  October  19th,  950  on  October  20th, 
600  on  October  21st,  600  on  October  22nd, 
400  on  October  23rd,  400  on  October  24th. 
In  spite  of  the  daily  administration  of  3  grams 
of  diuretin  the  quantity  of  urine  did  not  in- 
crease, but  remained  in  small  quantity.  On 
the  24th  of  October  it  was  400,  500  on  the 
25th,  500  on  the  26th,  400  on  the  27th,  400  on 
the  28th,  400  on  the  29th,  400  on  the  30th, 
400  on  the  31st,  400  on  November  1st,  600  on 
November  2nd,  600  on  November  3rd,  600  on 
November  4th,  600  on  November  5th,  600  on 
November  6th,  600  on  November  7th.  On 
November  5th,  epithelial  cells  were  found  in 
sediment;  no  albumin  or  casts.  In  this  man- 
ner the  condition  remained  until  December 
7th. 

Now,  through  the  investigations  of  Schlayer 
and  Takayasu,  we  know  that  vascular  hyper- 
susceptibility  in  vascular  nephritides,  may  re- 
main unchanged  even  after  a  year,  as  shown 
by  the  entirely  unchanged  character  of  the  dis- 
turbed excretory  conditions. 

It  is  further  known  that  the  elimination  of 
mercury  does  not  take  place  uniformly,  but 
on  the  contrary  in  an  irregular  manner.  Cor- 
responding to  the  above  are  the  toxic  symp- 
toms of  these  hypersusceptible  persons  in  re- 
missions and  exacerbations  (alternatives 

—  64  — 


8ALVAR8AN     FATALITIES 

d' ameliorations  et  de  vechutes,  Letulle). 
These  may  extend  through  many  months,  and 
indeed,  years.  Furthermore,  after  these"  long 
periods,  stomatitis,  enteritis  and  particularly 
mercurial  angina  in  the  Plaut- Vincent  form, 
with  exanthemata  may  recur. 

Quite  characteristic  is  the  following  case 
which  I  observed  some  time  ago.  Pat.  F.,  on 
account  of  syphilitic  manifestations,  was  rub- 
bed January  17th,  18th,  19th  and  20th,  1906, 
with  unguentum  ciner.,  3  grams  being  employ- 
ed each  time.  Directly  after  the  second  rub- 
bing fever  and  universal  reddening  of  the  skin 
appeared.  The  treatment  was  suspended  and 
with  bathing  and  powder,  the  manifestations 
disappeared.  Two  weeks  later  without  any 
further  antisyphilitic  treatment,  there  again  ap- 
peared an  extensive  reddening  of  the  skin,  and 
with  it  angina  and  very  high  fever.  The  pro- 
cess impressed  one  as  being  scarlet  fever.  No 
albumin  in  the  urine.  After  extensive  des- 
quamation  the  patient  was  discharged  cured 
on  March  7th,  1906.  From  June  1st  to  June 
27th,  the  patient  was  again  under  our  care  ex- 
hibiting the  same  serious  clinical  picture  as 
before.  Again  there  was  no  albumin.  Four 
days  after  discharge  again  the  same  symptoms 
supervened,  but  the  patient  did  not  present 
himself  at  the  hospital  until  July  2nd,  1906. 
Upon  complete  disappearance  of  the  typical 
mercurial  eruption,  on  account  of  a  persisting 
papular  eruption  of  the  scrotum  and  a  palmar 
psoriasis,  an  attempt  was  made  to  carefully  ad- 
minister mercury ;  on  August  7th,  at  1 1 :30, 
he  received  0.015  hydrar.  salicyl. 

Immediately    thereafter    the    patient    was 

—  65  — 


SALVARSAN     FATALITIES 

seized  with  headache,  chills,  and  rise  in  tem- 
perature; also,  by  2  o'clock  an  intense  exaiv- 
them  covering  the  entire  body  was  clearly  vis- 
ible. No  albumin  or  sugar  in  urine.  After 
recovery,  in  order  to  accustom  the  patient  to 
mercury,  he  was  given  a  capsule  of  mergal 
(divided  into  two  doses)  on  September  26th, 
28th,  30th  and  31st.  A  half  hour  after  the 
administration  of  each  dose  there  appeared 
headache,  a  sensation  of  heat,  reddening  and 
pruritus  over  the  entire  body. 

On  October  4th,  1906,  he  was  again  received 
by  us,  and  showed,  although  he  had  not  re- 
ceived any  mercury,  the  same  picture  of  der- 
matitis universalis  and  recurring  papular  erup- 
tion. He  was  treated  with  Zittmann's  decoc- 
tion. 

At  this  time  there  was  a  similar  case  in  my 
department  in  which  the  disturbance  of  diure- 
sis often  seen  in  these  cases,  became  well  es- 
tablished. Karl  W.,  23  years  old,  on  account 
of  syphilis,  received  from  his  physician  six 
injections  of  salicylate  of  mercury.  Follow- 
ing the  fourth  injection  an  eruption  made  its 
appearance,  for  the  treatment  of  which  the 
patient  was  received  into  the  Virchow  Hos- 
pital on  December  21st.  There  was  found  a 
general  dark  reddening  of  the  skin,  desquama- 
tion  of  the  skin  in  shreds ;  after  desquamation 
there  was  slight  weeping  of  the  desquamated 
areas.  The  urine  contained  albumin,  epi- 
thelial cells,  leucocytes  and  granular  casts 
in  moderate  quantity.  Finally  toward  the  end 
of  June  the  patient,  after  loss  of  hair  and  nails, 
was  fairly  well  cured,  although  much  reduced. 
On  account  of  positive  Wassermann  and  al- 

—  66  — 


SALVARSAN     FATALITIES 

terations  in  the  spinal  fluid  (Nonne  ++  Gold 
+  +  +  Cells  +  +  W.  500  per  cent.  0)  he  re- 
ceived in  July  seven  injections,  one  of  0.1,  one 
of  0.3,  five  of  0.2,  all  of  which  he  bore  with- 
out trouble. 

Without  renewal  of  the  mercurial  treatment, 
he  suddenly  took  sick  on  the  night  of  Octo- 
ber 12th,  showing  the  same  picture  of  a  gen- 
eral, slightly  weeping  mercurial  dermatitis. 
The  urine  was  at  this  time  free  from  albumin 
and  formed  elements.  However,  upon  admis- 
sion into  the  hospital  the  activity  of  the  kid- 
neys was  found  markedly  reduced,  and  later, 
coincidently  with  the  drying  of  the  skin  and 
disappearance  of  the  inflammation  after  des- 
quamation,  suddenly  developed  into  polyuria. 

October  14- 15th,  260  c.c.  sp.  gr.  1032. 

October  15-16th,  550  c.c.  sp.  gr.  1029. 

October  16-17th,  740  c.c.  sp.  gr.  1021. 

October  17- 18th,  2150  c.c  sp.  gr.  1010. 

October  18- 19th,  2500  c.c.  sp.  gr.  1012. 

In  about  this  way  the  urinary  secretion  re- 
mained until  November  5th,  when  the  patient 
was  completely  restored.  From  November  6th 
on  the  urine  was  normal,  and  on  November 
7th,  the  patient  was  given  y2  gram  of  iodide 
of  potassium.  It  was  normally  eliminated; 
urine  1500-1700  c.c.  with  sp.  gr.  of  1012-1016. 
On  November  13th,  0.1  and  on  November  16th, 
0.4  of  salvarsan  given  and  borne  without  the 
slightest  reaction. 

Such  exanthemata  may  take  place  under  dif- 
ferent provocations,  for  example  under  the  in- 
troduction of  salvarsan  in  the  presence  of 
damaged  kidneys.  In  this  manner  I  under- 
stand the  case  of  death  reported  by  Brauer. 

—  67  — 


8ALVAR8AN     FATALITIES 

In  general,  the  course  of  this  case  did  not  re- 
semble the  other  fatal  cases,  but,  on  the  con- 
trary, in  a  striking  manner  (nephritis  with 
granular  casts,  bloody  diarrhea,  no  convul- 
sions) the  descriptions  of  those  fatal  cases  fol- 
lowing the  use  of  insoluble  preparations  of 
mercury. 

S.,  34  years  old,  gardener,  well  nourished,  well 
muscled,  internal  organs  without  pathological 
changes,  denied  any  former  illness.  The  time  of 
infection  could  not  be  determined.  Chancre  on 
the  glans  since  January  14th,  1912.  Condition  on 
January  22nd,  1912:  Lesion  on  glans,  dis- 
seminated maculo-papular  exanthem,  papules  on 
the  margins  of  the  tongue  and  upon  the  tonsils. 
Wassermann  positive.  Under  the  direction  of  his 
private  physician  had  undergone  twelve  inunc- 
tions with  ungt.  cinereum  of  4  grams  each,  the 
last  of  which  was  on  February  2nd,  1912.  From 
February  6th  to  February  23rd,  patient  received 
one  calomel  injection  of  0.03,  five  calomel  injec- 
tions of  0.05.  On  account  of  stomatitis  treatment 
was  interrupted.  Urine  free  from  albumin.  On 
February  28th  given  one  injection  of  salvarsan, 
0.4.  In  the  afternoon  vomiting  and  diarrhea. 
March  6th,  second  injection  of  salvarsan  0.4  with 
diarrhea  following  in  the  afternoon.  On  the  same 
day  third  injection  of  salvarsan  given  (0.4)  with 
increase  of  diarrhea  and  vomiting.  On  March  7th 
diffuse,  in  places  confluent,  macular  eruption  of 
erythematous  nature.  Albumin  present  (marked 
opalescence),  a  few  hyaline  and  granular  casts. 
March  9th  exanthem  faded,  but  yet  recognizable. 
Today  fourth  injection  of  salvarsan,  0.4  given. 
March  10th,  exanthem  has  grown  more  marked 
reminding  one  of  the  Jarisch-Herxheimer  reaction 
occurring  in  syphilitic  exanthemata  treated  with  sal- 
varsan. Albumin  positive  (marked  opalescence). 
Few  hyaline  and  granular  casts.  March  12th, 
exanthem  extended.  Efflorescences  confluent, 
urticarial  in  character.  Desquamation  of  the 
hands.  March  16th,  exanthem  barely  perceptible; 

—  68  — 


SALVARSAN     FATALITIES 

flaky  desquamation  of  the  body,  that  of  the  hands 
in  larger  pieces  as  in  scarlet  fever.  Urinary  con- 
dition as  above.  March  18th,  eruption  completely 
gone.  Desquamation  of  the  hands  still  going  on. 
Wassermann  negative.  March  23rd,  for  two  days  a 
recent  disseminated,  and  confluent  urticarial, 
erythematous  exanthem.  Falling  of  the  hair. 
Temperature  38.5  C.  (101.4  P.).  Bloody  diarrhea, 
abdominal  pains,  urinary  condition  unchanged. 
March  25th  the  eruption  has  become  universal. 
March  26th  the  dermatitis  of  the  scrotum  and 
anus  is  "weeping."  Urine  as  above.  Temperature 
39.3  C.  (102.7  F.).  March  27th  universal  sero- 
fibrinous  dermatitis,  rhagades  over  joints.  Con- 
tinuous fever.  March  30th,  rhagades  on  other 
sites.  Desquamation  of  the  skin  over  large  part  of 
the  body,  disclosing  weeping  surface  beneath, 
especially  on  abdomen  and  back.  Blisters  on  the 
mucosa  of  tongue.  Diarrhea  and  marked  prostra- 
tion. Temperature  38.7  C.  (101.6  F.),  pulse  120. 
On  April  4th,  with  increasing  somnolence  and  in- 
crease of  temperature  to  40  C.  (104  F.),  death 
took  place.  The  skin  of  the  entire  body  resembled  a 
very  severe  burn  of  the  second  degree.  Postmor- 
tem (pathological  institute) :  Extensive  derma- 
titis, covering  entire  body.  Severe  parenchyma- 
tous  nephritis.  Slight  degeneration  of  the  heart 
muscle  and  liver.  Small  hemorrhages  in  the  mu- 
cous membrane  of  the  sigmoid  and  rectum.  Hy- 
peremia  of  the  lower  lobes  of  the  edema- 
tous  lung.  Enlargement  of  the  spleen.  Marked 
chronic  meningitis.  Very  marked  edema  of  the 
brain  and  moderate  edema  of  the  meninges.  The 
bladder  contains  about  700  cc.  of  urine.  Albumin 
positive  (opalescence) ;  occasional  erythrocytes 
and  leucocytes,  granular  and  hyaline  casts. 

With  its  serofibrinous,  general  character,  and 
merging  borders,  which  give  it  a  resemblance 
to  scarlet  fever,  the  exanthem  is  absolutely 
like  a  mercury-dermatitis.  The  salvarsan  der- 
matoses  are  always  lightly  spotted  or  are  uni- 
versal erythemata,  which  do  not  proceed  to 

—  69  — 


8ALVAR8AN     FATALITIES 

serous  infiltration  of  the  skin  and  to  a  char- 
acteristic desquamation.  Furthermore,  they 
do  not  have  the  long  duration. 

Just  recently  I  saw  an  exanthem  of  similar 
character  attributed  to  salvarsan.  A  young 
woman,  on  October  23rd,  1912,  received  at 
the  hands  of  a  dermatologist  a  salvarsan  in- 
jection which  was  well  borne.  Following  this, 
she  was  rubbed  with  six  capsules  of  gray  oint- 
ment. After  this  course  an  eruption  of  small 
water-filled  blisters  appeared.  On  December 
4th,  1912,  she  came  to  my  department  with 
universal  reddening  of  the  skin  and  large- 
flaked  desquamation,  that  from  the  feet  and 
hands  taking  the  form  of  a  glove. 

An  examination  of  the  desquamated  epider- 
mis on  December  8th,  that  is  six  weeks  after 
the  exhibition  of  the  mercury,  showed  the 
same  to  have  a  rich  mercury  content,  while 
arsenic  was  not  present.  The  urine  also  con- 
tained mercury. 

On  the  whole,  one  must  wonder  at  the  con- 
fusion of  many  physicians  in  regard  to  sal- 
varsan, for  so  many  of  them  attribute  to  sal- 
varsan an  effect  which  is  clearly  that  of  mer- 
cury. Thus  the  following  item  is  to  be  found 
in  the  Presse  Medicale,  No.  100,  December  4, 
1912: 

"Au  non  die  M.  Boulliard,  M.  Paul  Guillon 
presente  un  malade  atteint  de  syphilis  en  Aout 
dernier  pui  a  suivi  d'abord  un  traitement  mer- 
curiel,  puis  un  traitement  par  1'arseno-benzol, 
quinze  jours  apres  la  troizieme  injection 
d'arseno-benzol,  la  malade  accusa  une  derma- 
tite  exfoliante  generalisee  ainsi  qu'une  gen- 
givostomatitie  ulcereuse  aigue  et  persistante. 

—  70  — 


SALVARSAN     FATALITIES 

Dans  deux  autres  cas,  1'auteur  a  pu  constater 
semblables  lesions;  il  rapproche  celle-ci  des 
cas  de  gangrene  de  la  bouche  signales  par  M. 
Dritsky  et  recommande,  dans  le  traitement  par 
1'arseno-benzol  comme  dans  le  traitement  mer- 
curiel,  de  surveiller  attentivement  la  bouche 
des  malades." 

These  occurrences,  according  to  the  descrip- 
tion of  the  salvarsan  reactions  of  Neisser  and 
Hoffmann,  are  very  much  like  the  reactions  of 
mercurial  stomatitis. 

Zimmermann  who  describes  this  salvarsan 
reaction  on  the  teeth  from  the  Herxheimer 
clinic,  says : 

"For  a  long  time  we  have  been  able  to  ob- 
serve this  salvarsan  reaction  on  the  teeth,  and 
determined  that  it  usually  took  place  in  pa- 
tients who  had  a  more  or  less  severe  stomati- 
tis. It  is  a  matter  frequently  concerning  pros- 
titutes who  have  decayed  teeth,  and  in  whom, 
notwithstanding  the  most  careful  attention  to 
the  mouth,  a  severe  stomatitis  occurs  even 
after  small  doses  of  mercury. 

"The  pain  begins  suddenly,  often  just  after 
the  patient  has  left  the  operating  table.  In 
some  cases,  in  fact,  it  takes  place  before  the 
injection  is  finished.  The  pain  is  partly  local- 
ized in  certain  sites  (it  is  immaterial  whether 
especially  marked  stomatitic  changes  are  pres- 
ent or  not)  and  partly  as  a  boring  and  draw- 
ing, like  that  of  a  burn.  It  may  be  seated  at 
one  angle  of  the  jaw  and  then  suddenly  change 
to  the  other.  In  one  or  two  hours  the  pain 
entirely  ceases. 

"We  believe  these  phenomena  may  be  traced, 
perhaps,  to  a  sudden  destruction  of  spiro- 

—  71  — 


SALVARSAN     FATALITIES 

chaetes  in  the  teeth  and  mouth  and  the  libera- 
tion of  toxins  under  the  spirillocidal  influence 
of  the  salvarsan.  Since  a  stomatitis  is  highly 
favorable  to  the  above  process,  we  are  able 
to  understand  why  we  never  see  the  same  sort 
of  a  reaction  in  cases  of  syphilis  treated  solely 
with  salvarsan.  We  have  never  been  able  to 
establish  a  diminution  of  motility  of  spiro- 
chaetes  from  the  teeth  in  the  dark  field,  after 
an  injection  of  salvarsan." 

In  my  department  where  pure  salvarsan 
therapy  is  employed  such  reaction  never  pre- 
sent themselves.  Quite  convincing  that  these 
stomatitides  are  of  a  mercurial  nature  is  the 
circumstance  that  in  my  department,  to  which, 
at  my  request  a  dentist  was  appointed  to  take 
care  of  the  mouth  of  patients  undergoing  mer- 
curial treatment,  since  the  year  1910,  that  is, 
since  the  inauguration  of  my  policy  of  em- 
ploying salvarsan  alone,  mouth  disorders  have 
been  very  infrequent  and  the  dentist  is  the 
same  as  being  without  any  duties. 

These  observations  seem  to  indicate  that 
following  salvarsan  injections  reactions  may 
take  place  in  other  parts  of  the  body,  especially 
in  the  renal  arteries  or  other  small  vessels 
which  have  been  damaged  by  mercury  or  where 
mercury  still  remains  but  is  not  securely  an- 
chored in  the  tissues. 

One  must  consider  that,  as  the  excellently 
conducted  investigations  of  Moller  and  Blom- 
quist*  show,  the  capacity  of  the  kidney  to 
eliminate  mercury  from  the  system  is  rather 

*Dermatol.  Zeitschr.  Bd.  XVII,  H.  II  Veber  die 
Quecksilberausscheidung  durch  die  Nieren. 

—  72  — 


limited  and  marked  individual  deviations  may 
be  noted.  According  to  the  various  investi- 
gations of  Almkvist*  mercury  is  retained  in 
the  renal  cells  and  even  in  the  epithelial  cells 
of  the  collecting  tubules,  in  which  degeneration 
is  brought  about. 

How  such  foci  react  to  a  blood  current 
impregnated  with  salvarsan  we  do  not  know. 
Some  accounts  in  the  literature  speak,  with  a 
certain  plausibility,  of  an  occasional  explosive 
effect.  I  am  inclined,  in  general,  to  explain 
the  great  difference  in  opinion  of  various  au- 
thors in  writing  of  the  collateral  effects  of  sal- 
varsan, as  being  based  upon  different  modes  of 
treatment,  i.  e.,  the  pure  use  of  salvarsan  or 
the  combined  treatment. 

Concerning  this  I  cannot  add  anything  of 
special  import;  the  description  of  a  so  care- 
ful investigator  as  Gennerisch  does  not  cor- 
respond in  its  various  features  with  the  pic- 
ture of  the  consequences  of  salvarsan  injec- 
tions, as  we  usually  see  it. 

But  it  is  easy  to  understand  that  it  is  only 
in  certain  moments  that  the  employment  of 
salvarsan  is  dangerous,  especially  when 
through  mercury  a  vascular  oliguria  is  brought 
about  and  the  eliminative  function  interfered 
with. 

For  example,  my  assistant.  Dr.  Pakuscher, 
in  a  case  of  moderate  mercurial  nephritis,  was 
not  able  to  demonstrate  iodide  of  potash  which 
had  been  given,  in  the  urine  until  twelve  days 
had  elapsed. 

Very  recently  a  case  of  sublimate  poisoning 

*Dermatol.  Zeitschr,  Bd.  XIX,  H.  II. 
—  73  — 


8ALVARSAN     FATALITIES 

was  subjected  by  Conzen  to  the  newer  methods 
of  determining  renal  function.  Concerning 
this  Conzen  wrote  the  following: 

"The  glomeruli  are  fully  intact;  the  tubuli  are 
the  site  of  attack.  The  experimental  investiga- 
tions of  Schlayer  prove  functionally  that  there  are 
isolated  areas  of  tubular  defects.  Only  with  a 
quite  severe  damage  is  there  a  later  impairment 
of  the  function  of  the  glomeruli.  Consequently 
this  case  is  particularly  well  adapted  to  serve  in 
measuring  the  value  of  the  renal  tests. 

"CASE  12. — F.  M.,  31  years  old,  attempted  suicide 
on  January  7th,  1912,  by  drinking  a  glassful  of 
water  containing  one  gram  of  sublimate.  Im- 
mediately red  colored  material  was  vomited; 
in  the  evening  repeated  attacks  of  dizziness,  spots 
before  the  eyes,  further  wretching  and  vomiting  of 
bloody  masses.  During  the  night  and  on  the  next 
day  there  was  diarrhea.  Received  into  hospital 
on  January  8th.  At  this  time  strong  flow  of 
saliva,  burning  in  mouth,  difficulty  in  swallowing. 

"On  the  evening  of  the  7th,  after  evacuation  of 
a  small  quantity  of  urine  from  the  bladder,  com- 
plete suppression  set  in.  Not  until  January  14th 
was  any  urine  found  in  bladder  and  then  but  50 
cc.  It  was  light  in  color,  with  one  per  cent,  of 
albumin  and  containing  an  abundance  of  epi- 
thelial cells,  some  leucocytes  and  fragments  of 
hyaline  casts.  On  the  15th  and  16th  there  were 
further  diarrheal  passages  with  the  simultaneous 
discharge  of  an  extremely  small  quantity  of  urine, 
so  small  in  quantity  as  to  prevent  successful 
analysis.  On  the  17th  about  250  cc.  Albumin 
present  showing  a  distinct  cloudiness.  Micro- 
scopical examination  as  on  the  14th,  except  many 
granular  casts. 

"From  January  18th  until  March  8th,  and  then 
from  this  date  until  April  1st,  the  renal  powers 
were  uninterruptedly  under  observation. 

"The  quantity  of  albumin  still  small,  perceptible 
to  slight  clouding;  the  above  named  formed  ele- 
ments gradually  diminished.  The  blood  pressure 
always  remained  at  from  150  to  90  (the  high 

—  74  — 


SALVARSAX     FATALITIES 


blood  pressure  described  as  occurring  on  the  first 
day  of  sublimate  poisoning  was  not  noted  in  this 
case).  The  condition  of  the  heart  and  retina  re- 
mained normal. 

"From  January  22nd  on,  the  urinary  secretion 
corresponded  to  the  fluid  intake;  from  February 
1st  to  February  10th  somewhat  of  a  polyuria  ex- 
isted, then  normal  diuresis.  From  the  beginning 
the  sp.  gr.  was  1007  to  1014.  Just  once  it  reached 
1014.  During  a  right-sided  pneumonia,  upper 
lobe,  lasting  from  January  23rd  to  January  29th, 
and  during  a  consequent  miscarriage  (in  the  fifth 
month),  with  a  temperature  which  lasted  until 
February  3rd,  the  sp.  gr.  never  reached  above  1010. 

"The  further  discussion  will  concern  itself 
chiefly  with  the  period  between  January  18th  and 
January  29th. 

"With  an  average  intake  of  5  to  8  grams  of 
salt,  the  elimination  was  0.1  to  0.3  per  cent,  with 
an  absolute  quantity  of  1.5  to  4.8  grams;  it  was 
thus  too  low.  The  addition  of  10  grams  of  salt 
was  not  attempted,  it  not  being  thought  wise.  In 
view  of  the  above,  it  seems  undoubtedly  that  the 
case  was  that  of  tubular  impairment.  On  January 
23rd  and  27th  0.5  of  iodide  of  potassium  was 
given.  With  the  Sandow  test  I  was  unable  to 
produce  a  measurably  red  coloring  of  the  choloro- 
form.  Severe  damage  of  the  tubuli  therefore  evi- 
dent. On  January  25th  2  grams  of  lactose  intra- 
venously. Only  after  24  hours  was  elimination 
finished.  At  the  time  of  injection  the  pneumonia 
had  existed  for  two  days,  yet  the  urine  did  not 
contain  more  albumin  than  previously.  Also  the 
sediment  was  free  from  blood,  there  being  only  a 
few  leucocytes,  hyaline  and  granular  casts  and 
epithelial  cells. 

"Whether,  therefore,  a  glomerular  defect  caused 
by  the  pulmonary  infection  was  the  reason  for  the 
delayed  lactose  elimination  is  somewhat  doubtful, 
yet  this  should  not  be  dismissed  as  being  unworthy 
further  consideration.  That  blockage  of  the 
tubules  with  detached  epithelium  paralyzed  the 
filtration  power  of  the  otherwise  normally  func- 
tionating glomeruli,  with  interference  with  the 
elimination  of  the  lactose,  is,  in  view  of  the  re- 

—  75  — 


8ALVAR8 A N     FATALITIES 


storation  of  diuresis  in  a  week's  time,  scarcely  to 
be  accepted. 

"From  February  2nd  on,  the  absolute  and  per- 
centage quantities  of  salt  elimination  in  compari- 
son with  the  intake  reached  a  normal  figure,  so 
that  only  through  the  low  and  fixed  sp.  gr.  did 
t,ne  tubular  hyposthenuria  remain  in  evidence. 
An  additional  intake  of  10  grams  of  salt  which 
was  given  on  February  8th  was  almost  entirely 
retained.  The  elimination  of  about  3  grams  took 
place  not  in  an  increase  of  concentration  but,  on 
the  contrary,  through  a  slight  polyuria  extending 
over  several  days.  This  polyuria  had  already  been 
noticed  in  a  slight  degree  since  February  4th, 
which  was  the  first  day  on  which  the  patient  was 
free  from  fever.  Here  would  be  the  second  point 
which  might  possibly  indicate  a  slight  functional 
damage  of  the  glomeruli,  a  hypersusceptibility. 

"February  9th  0.5  iodide  of  potassium.  Elimina- 
tion in  53  hours,  therefore  occurring  in  the  normal 
variation  period.  How  this  prompt  iodide 
elimination,  at  a  time  of  existing  tubular  concen- 
tration-defect, is  to  be  explained,  I  am  not  able  to 
say. 

"February  llth  2  grams  of  lactose.  Elimination 
in  10  hours,  therefore  a  retardation  which,  how- 
ever, did  not  correspond  to  a  glomerular  nephritis 
due  to  the  pneumonia  or  miscarriage. 

"February  14th,  increase  in  water  intake; 
eliminated  in  24  hours. 

"February  25th,  10  grams  of  salt  added  to  usual 
salt  intake.  Eliminated  in  48  hours  and  through 
increase  in  concentration. 

"March  21st  and  31st,  again  10  grams  of  salt. 
Although  not  eliminated  in  entire  quantity  (5.5 
and  7  grams)  yet  excretion  secured  through  in- 
crease in  concentration. 

"March  19th,  0.5  iodide  of  potassium  eliminated 
in  49  hours. 

"March  23rd,  2  grams  of  lactose  eliminated  in  6 
hours. 

"March  25th,  increase  in  water  intake.  Elimin- 
ated in  24  hours.  A  fixed  and  low  sp.  gr.,  but  no 
polyuria.  Trace  of  albumin  in  urine.  Since  March 

—  76  — 


8ALVARSAN     FATALITIES 


7th  no  casts  and  leucocytes,  only  abundant  epi- 
thelial cells. 

"Regarding  the  reaction  of  the  urine;  •  from 
January  18th  to  February  3rd  that  is,  to  the  end 
of  the  fever,  it  was  slightly  acid,  from  then  the 
acid  values  grew  somewhat. 

"With  the  salt  addition  on  February  25th  and 
on  March  21st  and  31st,  an  increase  in  albumin 
was  noted  each  time,  but  without  change  in  the 
diuresis  or  general  condition  of  the  patient. 

"Since  the  elimination  of  albumin  takes  place 
through  the  glomeruli,  then  of  course  it  is  here 
we  would  look  for  disease  when  albumin  is  noted. 

"In  a  case  of  poisoning  with  sublimate  there  is 
a  pronounced  and  severe  damage  done  to  the 
tubuli  (tubular  hyposthenuria;  iodide  elimination 
rather  markedly  retarded)  which  is  demonstrable 
only  until  about  the  middle  of  the  4th  week  after 
the  ingestion  of  the  poison.  This  shows  itself  in  a 
reduction  of  concentration-power  but  not  in  re- 
tardation of  iodide  elimination;  the  functional  im- 
pairment of  the  tubuli  exists  for  several  months, 
at  least,  after  poisoning. 

"A  retardation  of  lactose  elimination  manifested 
itself  as  long  as  11  weeks  after  the  infliction  of  the 
damage  done  by  the  sublimate.  At  the  beginning 
this  was  marked  and  associated  with  mild  poly- 
uria.  It  was  not  shown  that  the  pneumonia  or 
miscarriage  (as  mentioned  in  the  above  case), 
could  have  given  rise  to  the  acute  glomerular 
nephritis. 

"Taken  together  with  the  excretion  of  albumin 
upon  the  increase  of  salt  intake,  the  results  of  the 
functional  tests  indicate  that  in  sublimate  poison- 
ing in  humans  besides  the  anatomical  damage  done 
to  the  tubuli,  a  functional  impairment  of  the 
glomeruli  is  also  to  be  assumed." 

To  what  extent  only  a  temporary  insuffi- 
ciency influences  the  accidents  which  are  at- 
tributed to  salvarsan  may  be  seen  in  the  fact 
that  frequently  the  same  accidents,  that  is 
to  say  the  epileptiform  attacks  and  even  coma 

—  77  — 


8ALVAR8AN     FATALITIES 

itself,  may  be  overcome  and  then  later  salvar- 
san  again  administered  without  evil  result.  A 
case  in  point  is  that  reported  by  Milian:  A 
young  officer  received  0.6  of  salvarsan,  four 
days  after  which  coma  supervened  and  for  a 
week  amnesia  existed.  However,  later  the  pa- 
tient tolerated  injections  of  salvarsan,  respec- 
tively, 0.2,  0.3  and  0.4  without  reaction.  Quite 
recently  Bettmenn*  has  published  a  similar 
case.  A  24-year-old  carpenter  received  on 
May  29th  and  June  4th,  each,  a  dose  of  0.75 
neosalvarsan.  On  June  7th,  without  warning 
the  patient  fell  to  the  ground  senseless.  Pupils 
without  reaction,  vomiting,  irregular  pulse. 
The  condition  lasted  for  several  hours;  re- 
covery then  followed.  Albumin  in  urine.  Pa- 
tient had  been  under  mercury.  On  July  6th, 
0.45  neosalvarsan  was  given  without  reaction. 

A  similar  case  occurred  in  the  practice  of 
Dreyfuss,  which  was  reported  by  Ehrlich.** 

To  this  category  belong  those  cases  which 
are  cured  after  lumbar  puncture.  This  meas- 
ure operates  very  frequently,  as  reported  in 
gynecological  publications,  as  a  life-saving  pro- 
cedure in  eclampsia  and  uremia,  that  is  clinic- 
ally similar  conditions.! 

Walter  Freyff  has  also  recently  written  from 

*Muncher  med.  Wochen.  1912,  No.  43. 
**Abhandlungen  zur  Salvarsantherapie,   Bd.   II, 
XXX  S.  583. 

"\KorrespondenzWatt  f.  Schweizer  Aerzte,  1912, 
No.  17. 

tt  Compare  Parades,  due  coma  et  de  la  ponction 
lombaire.  These  Montpellier,  1912.  Further,  in 
Gesammelte  Abhandlungen  zur  Salvarsantherapie, 
Bd.  II,  S.  600,  the  cases  of  Meirowsky  and  Spiel- 
hoff. 

—  78  — 


SALVARSAN     FATALITIES 

the  Basle  clinic  concerning  lumbar  puncture 
in  the  presence  of  the  cerebral  type  of  ure- 
mia. 

According  to  all  experience  up  to  the  present 
time,  one  is  warranted  in  accepting  the  con- 
clusion that  a  normal  kidney  is  never  func- 
tionally damaged  by  salvarsan,  but  that,  on 
the  contrary,  disturbances  of  salvarsan  elimin- 
ation take  place  only  with  already  diseased 
kidneys. 

It  is  also  becoming  clear  why  the  acute  and 
subacute  inflammations  of  the  kidney,  for  ex- 
ample those  due  to  mercury,  in  general  are 
more  dangerous,  even  though  the  pathological 
changes  are  less,  than  the  chronic  nephritides. 
In  these  toxic  renal  inflammations  the  entire 
kidney  is  concerned,  glomeruli  and  tubuli  suf- 
fering a  certain  damage  in  common,  whereas 
in  the  chronic  nephritides  the  disease  is  focal 
or  patchy  alongside  of  completely  functionat- 
ing areas,  which  even  take  on  a  compensatory 
activity. 

One  must  remember  that  while  such  kid- 
neys may  the  first  time  successfully  carry  on 
salvarsan  elimination,  yet  through  the  burden 
so  extensive  a  functional  impairment  may  be 
inflicted  upon  the  vessels  that  with  the  sec- 
ond injection  of  salvarsan  its  elimination  and 
also  that  of  the  urinary  substances  is  seriously 
disturbed.  Dreser  injected  animals  with  acid 
fuchsin  following  which  the  urine  became  red 
colored,  while,  at  the  same  time,  the  renal  cells 
remained  uncolored.  With  the  second  injec- 
tion of  this  character  the  cells  of  the  urinifer- 
ous  tubules  became  colored.  The  cells  be- 
come wearied  and  damaged.  Likewise,  as  a 

—  79  — 


SALVAR8AN     FATALITIES 

result  of  a  temporary  ligature  of  the  renal  ar- 
tery, renal  cells  retain  the  color.  Heidenhain, 
Nussbaum  and  Graetzer  have  shown  the  same 
to  hold  good  with  indigo-sodium  sulphate 
(Martin  Fischer,  Nephritis). 

We  have  already  pointed  out  that  the  clin- 
ical and  pathological  picture  of  salvarsan  fa- 
talities does  not  agree  with  that  of  arsenical 
poisoning.  Even  less  so  does  it  resemble  the 
picture  of  a  fatal  case  of  uremia;  it  is  much 
more  likely  caused  by  salvarsan  retained  in  the 
blood  or  in  the  tissues  in  consequence  of  the 
renal  insufficiency.  A  clear  conception  of  the 
process  is  given  by  the  investigations  of  An- 
drews who  showed  at  Ehrlich's  institute  that 
mice,  to  which  salvarsan,  arsenophenylglycin, 
sublimate,  akridinsal  and  salicylarsenmethy- 
lester,  are  given  and  which  are  then  injected 
with  sulphorhodamin,  a  rose  red  coloring  ma- 
terial, do  not  eliminate  the  coloring  material  in 
case  the  poison  has  caused  renal  insufficiency, 
and  they  die  within  24  hours. 

Several  factors  indicate  that  the  exanthe- 
mata of  salvarsan  as  well  as  those  of  mercury, 
play  a  part,  in  the  presence  of  temporary  ces- 
sation of  the  renal  function,  in  the  vicarious 
elimination  of  the  remedial  agent  by  means  of 
the  skin. 

Following  every  injection  of  salvarsan  the 
substance  circulates  in  the  blood,  and  the 
question  arises,  how  is  it  that  the  usually  inno- 
cent material  may  suddenly  take  on  a  poison- 
ous nature?  Ostwald  has  compared  salvarsan 
to  a  snapping  dog  carrying  a  muzzle.  The 
question  is,  under  what  circumstances  does 
salvarsan  slip  its  muzzle?  If  we  observe  the 

—  80  — 


SALVARSAN     FATALITIES 

type  of  innocuous  arsenic  combinations — Bun- 
sen's  cacodyl — then  we  see  that  this,  as  point- 
ed out  by  Schulz,  becomes  poisonous  so  soon 
as  the  cacodyl  combination  remains  for  a  long- 
er period  than  usual  in  the  body.  Miiller, 
Schoeller  and  Schrauth  consider  that  the 
(chronic)  poisonous  action  of  the  organic 
mercury  products  is  the  resultant  of  the  quick- 
ness of  elimination  and  the  ease  with  which 
the  complex  preparations  are  broken  up ;  they 
understand  thereby  mercury's  power  to  disas- 
sociate itself  from  its  combination  and  to  af- 
fect the  body.  Now  we  know  that  in  the  ma- 
jority of  instances,  salvarsan  is  quickly  elim- 
inated from  the  organism,  while  arsenic  re- 
mains somewhat  longer  in  the  body,  especial- 
ly in  the  liver  and  the  musculature.  If  a  de- 
composable substance  goes  quickly  through  the 
body  then  it  can  easily  be  innocuous ;  but  on 
the  other  hand,  let  it  go  through  slowly,  then 
chemical  changes  consequent  upon  the  longer 
duration  of  elimination  become  inevitable,  and 
under  certain  circumstances  the  agent  may  be- 
come poisonous.  Through  Heffter's  investi- 
gations of  the  retention  of  cacodylic  acid  in 
the  organism,  it  is  established  that  a  number 
of  animal  organs  (liver,  stomach  and  bowel) 
contain  substances  which  are  endowed  with  an 
energetic  power  of  reduction  and  are  able  to 
reduce  cacodylic  acid  with  the  formation  of 
cacodyloxid.  It  is  therefore  probable  that  sal- 
varsan with  a  long  retention  in  the  body  also 
undergoes  such  reduction.  In  the  case  of  the 
more  easily  decomposed  neosalvarsan  this 
probably  occurs  more  often  than  with  old  sal- 
varsan. 

—  81  — 


In  his  memorable  address  on  October  31st, 
1909,  before  the  German  Chemical  Society, 
Ehrlich  offered  information  on  the  toxicity  of 
products  in  the  organism  originating  in  the  re- 
duction of  arsanil. 

It  is  a  well  known  fact  that  in  the  compound 
Arsanil,  the  oxygen  carrying  complex  of  ar- 
senic attached  to  the  benzene  ring  (or  benzol 
ring)  is  pentavalent,  hence  Arsanil  is  to  be 
considered  as  an  aromatic  acid  of  arsenic.  Now 
it  became  necessary  to  convert  this  substance 
into  the  products  obtained  by  reduction  in 
which  arsenic  appears  as  a  trivalent  element 
(analogous  to  arsenous  acid,  As2  Os  also  called 
arsenic  trioxide). 

Following  a  new  line  of  procedure  Pro- 
fessor Bertheim  and  myself  have  succeeded  in 
obtaining  two  distinct  products  according  to 
the  relative  strengths  of  the  various  reducing 
agents  employed,  which  correspond  to  those 
produced  and  ascribed  by  Michaelis  to  the 
graded  stages  of  reduction  of  phenylarsenious 
acid,  namely: 

1.  The  monomolecular  As  O — product, 
white  in  color  and  soluble  in  acids  and  alkalis, 
the  p-aminophenylarsenous  oxid, 

As=O 


y 

NH2 

and 

2.    The  product  obtained  by  further  reduc- 

—  82  — 


8ALVAR8 A N     FATALITIES 


tion,  whereby  through  condensation  of  two 
molecules  of  the  first  described  compound  an 
entirely  new  compound  of  arsenic  is  produced, 
the  yellow  diaminoarsenobenzene,  soluble  only 
in  acids; 


As=As 


NH2  NH2 

The  toxicological  character  of  the  sub- 
stances is  radically  changed  through  the  above 
described  process  of  reduction.  It  has  been 
shown  that  the  highest  toxicity  is  always  ob- 
tained in  compounds  in  which  the  element  ar- 
senic in  union  with  oxygen  occurs  trivalent 
(As  O — ).  To  become  considered  as  import- 
ant is  the  relative  nontoxic  character  of  the 
arseno  compounds  of  glycine. 

Relative  Toxicity  of  the  products  of  reduction. 
(Lethal  dose.) 


(Sod  i  u  m 
salts     of) 
Arsinacid. 

As  O— 
com- 
pounds. 

Arseno 
com- 
pounds. 

1.  NH2 
2.  OH. 
3.  NH.    CH2 
.COOH. 

1:200 
1:75 

1:20 

1:15,000 
1:13,000 

1:1000 

1:7000 
1:1000 

1:70 

The  above  indicates  the  degree  of  dilution  of 
which  exactly  1  c.cm.  is  capable  of  killing  a  mouse 
weighing  20  grams. 

—  83  — 


SALVARSAN     FATALITIES 

His  Excellency  Professor  Ehrlich  has  kind- 
ly placed  at  my  disposal  his  views  relative  to 
the  theory  as  to  the  changes  which  may  take 
place  in  the  composition  of  salvarsan. 

Through  chemical  influences  three  distinct 
compounds  may  be  obtained  from  salvarsan, 
in  which  the  substance  occurs  as  an  arseno- 
compound : 

1st.  Through  further  reduction  a  compound 
is  formed  which  Ehrlich  calls  Phenylarsin, 
which  is  analogous  to  Arsin  also  called  ar- 
senuretted  hydrogen  (As  Hs) 

As  H2 


NH2 

OH 

We  have  tested  this  compound  known  as 
Phenylarsin,  the  dose  of  which  is  0.1,  and 
have  found  the  same  more  toxic  but  also  more 
active  than  salvarsan.  The  formation  of  a 
compound  as  Phenylarsin  in  the  animal  body 
is  practically  an  impossibility  as  the  substance 
is  only  formed  under  the  most  powerful  re- 
ducing influences. 

2nd.  On  the  other  hand  there  is  a  possi- 
bility of  the  formation  of  a  compound  which 
Ehrlich  calls  "Arsenoxide,"  through  the  oxi- 
dation of  salvarsan,  which  is  a  substance  far 
more  toxic  in  character  than  the  previously 
described  product,  Phenylarsin. 
—  84  — 


8ALVAR8AN     FATALITIES 

As  O 

NH2  /\ 

(Arsenoxide) 


OH 


:<  'Arsenoxide'  is  readily  formed  by  expos- 
ing the  alkaline  solution  to  the  air,  and  in  my 
personal  opinion  this  'Arsenoxide'  is  the  chief 
cause  of  the  serious  reactions  so  often  com- 
plained of.  In  support  of  this  statement  I  am 
relying  upon  the  experiences  which  were  ex- 
tensively described  and  related  in  the  first  ex- 
periments and  observations  with  arsenophenyl- 
glycin  disturbances  occurred  in  the  beginning; 
one  case  resulted  fatally.  The  disagreeable 
manifestations  were  probably  caused  by  my 
first  method  in  preserving  the  arsenophenyl- 
glycin  in  which  at  least  ten  per  cent,  of  cases  of 
serious  disturbances  occurred  in  the  beginning ; 
glycin  in  ordinary  stoppered  bottles  instead 
of,  as  now,  in  vacuo" 

"It  is  my  belief,"  says  Prof.  Ehrlich,  fur- 
ther, "that  the  interference  with  the  renal 
function  which  you  presume  exists,  is  occa- 
sioned by  the  retention  of  salvarsan  in  the  or- 
ganism or  blood,  which  favors  the  formation 
of  the  more  dangerous  arsenoxide.  At  least 
it  seems  almost  proven  that  certain  easily  oxy- 
dizable  substances  which  under  ordinary  con- 
ditions do  not  color  animals,  cause  a  distinct 
bluish  coloration  of  the  body  of  animals  which 
receive  too  large  a  dose  of  the  substance  which 
consequently  causes  an  inhibition  of  proper 

—  85  — 


8ALVARS AN     FATALITIES 

elimination  of  the  drug.  There  occurred  then 
a  biological  oxydation,  and  this  I  prefer  to  ac- 
cept in  explanation  of  the  unhappy  effects  fol- 
lowing salvarsan." 

3.  "The  Arsenoxide  can  be  still  further 
oxidized,  to  phenylarsin  acid.  I  believe,  how- 
ever, that  this  is  but  rarely  the  case;  at  any 
rate  such  an  extensize  oxydation  cannot  be 
drawn  upon  to  furnish  an  explanation  of  death 
since  the  p-Oxymetamidophenylarsinacid  is 
much  less  toxic  than  salvarsan  and  in  the  em- 
ployed dosage  must  be  considered  as  without 
danger." 

Salvarsan  which  has  undergone  decomposi- 
tion causes  renal  damage  and  anuria.  Thus 
Eitner  saw  an  anuria  lasting  two  or  three  days 
in  a  patient  in  whose  case  the  salvarsan  pow- 
der, employed  for  injection,  had  been  exposed 
for  two  weeks  to  the  air.  Malinowski  saw  an 
anuria  lasting  for  ten  days  following  an  in- 
jection of  salvarsan  which  had  been  exposed 
for  five  days  to  the  air.  Jakimoff  demon- 
strated experimentally  the  -increased  toxicity 
of  oxydized  salvarsan  for  the  kidneys.  Con- 
cerning this  point  we  shall  later  by  means  of 
exact  investigations  secure  an  explanation  of 
fatal  poisoning.  As  the  picture  of  this  pois- 
oning does  not  correspond  to  the  poisoning  by 
arsenic,  then  it  must  be  determined  whether 
the  groups  which  are  related  to  arsenic  do  not 
cause  the  poisoning  following  decomposition. 
Sabbattini,*  in  this  connection,  has  made  many 


*Physikalische  Betrachtungen  iiber  toxiscJie  Hg. 
Wirkungen.  Biochem.  Zeitschrift,  1908,  337, 
Festschrift  fur  Hamburger. 

—  86  — 


SALVARSAN     FATALITIES 

striking  experiments  relating  to  the  complex 
mercury  combinations  and  their  division. . 

As  must  always  be  emphasized,  salvarsan 
fatalities  do  not  resemble  arsenical  fatalities. 
But  they  do  have  a  close  resemblance  to  deaths 
caused  by  carbon  monoxide.  Here  we  find 
the  same  clinical  picture,  headache,  convul- 
sions, vomiting,  unconsciousness,  coma,  invol- 
untary passages  of  urine  and  feces,  etc.* 

The  old  investigations  of  Klebs**  particularly 
show  a  close  analogy ;  from  three  cases  com- 
ing to  autopsy  he  pictured  the  last  stage  as 
presenting  deep  coma,  marked  dyspnea  and 
cyanosis,  which  are  so  frequently  mentioned 
in  descriptions  of  salvarsan  fatalities,  added 
there  to,  in  the  first  and  third  case,  tetanic 
muscular  rigidity  and  muscular  twitchings 
with  fully  accelerated  pulse.  Especially  strik- 
ing was  the  extraordinary  abundance  of  blood 
in  all  regions.  He  particularly  mentions  the 
fine  capillary  congestion  of  the  brain,  especi- 
ally of  the  gray  matter;  and  in  the  kidneys 
and  liver  an  injection  of  so  marked  a  charac- 
ter as  to  be  comparable  only  to  an  artificial 
injection  of  the  vessels.  It  is  not  encephalitis 
hemorrhagica  but,  on  the  contrary,  the  enor- 
mous distension  of  the  vessels  which  is  the 
constant  finding  in  death  from  salvarsan. 

The  cyanosis  and  dyspnea  in  salvarsan  fa- 
talities, which  occurred  in  a  particularly  char- 
acteristic manner  in  the  case  of  Busse  and 
Merian  and  which  were  effectively  combated 
with  inhalations  of  oxygen,  show  plainly  that 

*Kunkel.   Toxikologie,  s.  336. 
**Wirkungen    des    Kohlenoxydes    auf    tierschen 
Organismus.     Virchow's  Arch.  Bd.  32,  s.  450. 

—  87  — 


SALVARSAN     FATALITIES 

one  should  not  lose  sight  of  the  possibility  of 
disturbance  of  respiratory  innervation.  One 
is  also  reminded  somewhat  of  the  "red  as- 
phyxia" of  Claude  Bernard.  Through  this 
then  also  the  cerebral  irritation  (convulsions, 
paralysis,  coma)  could  easily  be  explained.  It 
is  generally  known  how  violently  the  central 
nervous  system  reacts  to  interferences  with 
its  supply  of  oxygen.  In  carbon  dioxide 
poisoning  the  most  conspicuous  findings  are 
the  capillary  hemorrhages  in  the  brain,  and 
foci  of  softening.  It  must  again  be  empha- 
sized that  purpura  of  the  brain  and  encephali- 
tis hemorrhagica  are  not  characteristics  of  ar- 
senical poisoning.  These  do  not  depend  upon 
capillary  thrombi,  as  could  occur  in  arsenic 
poisoning,  but  upon  diapedesis  through  dam- 
aged blood  vessels.*  In  conjunction  with  Dr. 
Pakuscher  I  have  examined  several  cases  of 
encephalitis  hemorrhagica  after  salvarsan  with 
the  greatest  exactness,  reaching  my  former 
conclusion  that  this  could  depend  upon  emboli, 
yet  at  the  same  time  I  did  not  omit  careful  at- 
tention to  the  possibility  of  thrombi  but  with 
negative  results. 

An  exception  to  this  view  occurs  in  the  case 
of  Marschalko  and  Veszprem.** 

*Martin  B.  Schmidt  (I.  c.)  cites  a  case:  Jerome 
Schneider,  21  years  of  age,  was  treated  for  11  days 
in  the  skin  clinic  at  Heidelburg  with  chrysarobin 
and  arsenic.  Just  as  he  was  about  to  be  dis- 
charged he  was  suddenly  seized  with  headache  and 
unconsciousness,  dying  in  36  hours.  Autopsy: 
Ecchymoses  in  brain  and  endocardium.  Hyper- 
emia  of  the  kidneys  and  other  abdominal  organs. 
One  could  scarcely  attribute  this  mysterious  death 
to  arsenic  poisoning. 

**Deutsche  med.  Wochen.     1912,  26. 

—  88  — 


SALVARSAN     FATALITIES 

A  38-year-old  state's  official  received  at  the 
hands  of  his  physician  on  November  10th, 
1911,  an  intravenous  injection  of  0.53  salvar- 
san  which  was  made  up  with  distilled  water 
that  was  not  fresh.  In  two  hours  the  patient 
became  ill  with  vomiting,  but  this  soon  passed 
away.  On  the  next  morning  there  occurred 
chills,  temperature  of  40  C.  (104  Fahr.),  and 
vomiting;  on  the  14th  unconsciousness,  tem- 
perature 36.5  C.  (97.7  Fahr.),  epileptiform  at- 
tack, etc.  Death  five  days  after  injection. 

Encephalitis  hemorrhagica  without  purulent 
infiltration.  The  capillaries  partly  distended 
with  uniform,  hyaline  thrombi,  and  also  in 
some  of  the  largest  vessels  pronounced  thrombi 
of  the  vessel-walls  were  found. 

Unfortunately  the  functional  power  of  the 
kidneys  and  the  condition  of  the  chorioidal 
plexus  was  not  observed.  But  it  is  fair  to  as- 
sume that  damage  occurred  in  the  kidney 
through  toxic  action  of  the  drug  permitting 
an  abnormal  permeability  of  the  capillary 
walls.  (Magnus,  Bildung  der  Lymph,  in  Op- 
penheimer,  Biochemie,  II,  2.) 

But  the  resemblance  extends  still  further, 
in  that  in  carbonic  acid  gas  poisoning  and  focal 
softening,  these  hemorrhages  are  most  fre- 
quently to  be  found  in  the  larger  basal  gang- 
lia especially  in  the  lenticular  nucleus,  there- 
fore exactly  as  in  salvarsan  poisoning. 

Polchen  aptly  explained  this  peculiarity  of 
carbon  dioxide  poisoning.  "The  carbon  diox- 
ide circulating  in  the  blood  impairs  the  nour- 
ishment of  the  vessels  and  thereupon  follows 
necrobiosis."  So  we  see  fatty  or  hyaline  (sal- 
varsan) changes  of  the  same,  but  no  thrombi. 

—  89  — 


SALVARSAN     FATALITIES 

"Especially  the  vessels  of  the  regio  innominata 
and  of  both  the  inner  limbs  of  the  lenticular 
nucleus  become  diseased,  because  these  ves- 
sels at  their  origin  are  extraordinarily  small, 
and  very  long,  5  to  5  cm.  without  anastomo- 
sis and  without  vasa  vasorum,  and  thus  solely 
dependent  upon  the  blood  circulating  through 
their  lumina  for  sustenance.  The  narrower 
the  vessels  become,  the  more  deleterious,  nat- 
urally, becomes  the  poisoned  blood;  thus  we 
found  the  vessel  walls  close  by  to  the  broad 
trunk  of  the  middle  cerebral  artery,  still  in- 
tact."* 

It  struck  Klebs  as  strange  that  in  carbon 
dioxide  poisoning  the  trunks  of  the  cerebral 
vessels  are  strikingly  tortuous,  especially  the 
finer  branches,  and  he  gives  a  convincing  de- 
scription of  the  microscopical  appearance.  He 
explains  the  lengthened  and  tortuous  condition 
of  the  vessels  through  an  atony  of  the  vessels 
caused  by  the  poison,  in  which,  however,  by 
reason  of  the  strong  systolic  force  of  the  heart, 
an  abundance  of  blood  is  circulated.  He  ex- 
plains this  phenomenon,  'especially  as  it  oc- 
curs in  the  meningeal  artery,  thus :  "While  in 
elastic  tissues,  such  as  the  lungs  or  spleen,  an 
increase  of  arterial  contents  causes  an  increase 
in  size  of  the  entire  organ  without  disloca- 
tion or  change  of  position  of  the  vessels,  and 
in  more  solid  tissues,  renal  for  instance,  on 
account  of  the  intimate  connection  of  vessel 
wall  and  parenchyma  in  general  no  dislocation 
of  either  part  takes  place,  the  wall  of  the  men- 

*Zur  Aetiologie  der  Gehirnerweichungen  nach 
Eohlendunstvergiftung.  Virchow's  Archiv,  Bd.  s. 
26. 

—  90  — 


SAL VAR8 AN     FATALITIES 

ingeal  artery  with  its  adventitia  lies  as  if  in 
a  canal,  in  the  dura  mater,  the  rigid  wajls  of 
which  do  not  give  before  the  impact  of  the 
pulsation." 

In  the  future,  therefore,  in  cases  of  salvar- 
san  poisoning,  one  must  direct  his  view  more 
than  formerly  to  the  state  of  the  blood  current, 
especially  as  concerns  its  oxygen  content;  for 
salvarsan  is  an  exceptionally  potent  reducing 
agent,  as  shown  histologically  by  Tryb* 
through  the  delicate  methods  of  Unna  and 
Golodetz. 

According  to  what  has  been  said,  in  the 
future  one  will  have  to  employ,  when  adminis- 
tering intravenous  injections  of  salvarsan,  the 
utmost  care  in  estimating  the  renal  function. 
Our  observations  relating  to  this  matter  with 
pure  salvarsan  therapy,  show  that  in  general 
in  such  cases  diuresis  is  of  a  normal  type; 
only  now  and  then  does  it  reach  a  stage  of 
polyuria  and  but  seldom  does  the  quantity  of 
urine  sink  to  as  low  as  600-800  c.cm.  In  later 
cases  we  have  frequently  seen  the  injection  of 
salvarsan  responded  to  with  headache,  vomit- 
ing and  exhaustion,  and  therefore  we  exercise 
the  greatest  care  concerning  the  dosage  and 
frequency  of  injection.  With  the  combined 
treatment  still  greater  care  must  be  shown. 

After  the  first  injection  of  salvarsan,  which 
for  the  purpose  of  testing  the  idiosyncrasy  of 
the  patient  should  not  be  in  excess  of  0.1  or 
0.2,  one  must  always  pay  strict  attention  to 
diuresis.  In  our  department  even  a  minimum 
reaction  or  slight  increase  in  temperature  oc- 


*Monatshefte  f.  prakt.  Dermat.  Bd.  52,  s.  406. 
—  91  — 


8ALVAR8AN     FATALITIES 


•%Z.O 


°%z.o 


»%20 


s      * 


II 


Ik 


—  92  — 


8ALVA R8 AN     FATALITIES 

curs  with  great  rarity;  even  following  the 
first  injection  such  phenomena  seldom  occur. 
We  carefully  investigate  every  reaction,  even 
the  slightest,  and  extraordinarily  frequently 
we  find  a  dependence  of  the  reaction  upon  im- 
pairment of  renal  function.  As  a  paradigm 
let  me  cite  the  following  case: 

A  33-year-old  woman,  suffering  with  a  luetic 
stricture  of  the  rectum,  who  had  been  frequently 
treated  with  mercury,  urine  free  from  albumin,  re- 
ceived 0.1  salvarsan  on  November  14th,  1912.  Tem- 
perature at  this  time  37.6  C.  (99.6  Fahr.).  Novem- 
ber 15th  37.6  C.  (99.6  Fahr.). 

See  chart  III.* 

We  have  observed  the  same  in  hypoplasia 
of  the  heart  with  oliguria. 

It  is  also  to  be  noted  that  long  continuing 
infectious  diseases,  diphtheria  and  scarlet  fever 
above  all,  can  leave  in  their  wake  a  vascular 
hyposthenuria. 

Just  recently  we  saw  a  young  girl  with  oc- 
cult syphilis,  who  showed  a  positive  Wasser- 
mann  and  who  had  never  been  treated,  fol- 
lowing an  injection  of  0.1  salvarsan  on  Novem- 
ber 15th,  develop  a  temperature  of  39.6  C. 
(103.2  Fahr.).  Then  oliguria  without  albu- 
min occurred.  On  November  16th,  amount 
of  urine  passed  700  c.cm.,  sp.  gr.  1024;  No- 
vember 17th,  200  c.cm.  (!)  sp.  gr.  1028,  No- 
vember 18th,  400  c.cm.  sp.  gr.  1030,  Novem- 
ber 19th,  500  c.cm.  sp.  gr.  1030.  Presumably 

*Also  the  next  injection  of  0.1  of  salvarsan  was 
responded  to  with  exactly  the  same; reaction.  One 
can,  very  easily  believe  that  such  a  patient,  if  re- 
ceiving two  or  three  injections  of  0.4-0.6  salvarsan 
might  not  eliminate  tue  drug. 

—  93  — 


8 A L V A R 8  A N     FATALITIES 


—  94  — 


SALVARSAN     FATALITIES 

the  cause  for  the  drop  in  the  functional  curve 
was  a  diphtheritic  attack  suffered  in  1911. 

It  is  clear  that  the  damage  to  renal  vessels 
which  produces  polyuria  is  of  a  moderate 
grade,  while  that  which  is  associated  with  oli- 
guria  represents  a  severer  grade.  It  is  prob- 
able— further  proof  on  this  point  must  be 
worked  out — that  only  with  severe  damage  to 
the  kidney  is  there  sufficient  interference  with 
the  elimination  of  salvarsan  to  produce  a  men- 
acing state.  Practically  speaking,  then  it  is 
only  oliguria  which  is  to  be  considered  in  the 
question  when  confronted  by  a  death  after 
salvarsan.  Whether  the  lighter  grades  of 
damage  to  the  renal  vessels,  they  can  mani- 
fest themselves  in  an  increase  or  even  a 
(pseudo)  normal  quantity  of  urine,  have  a 
practical  significance  can  only  be  determined 
by  further  observations.  If  no  absolute  stand- 
ard of  the  functional  power  of  the  renal 
vessels  can  be  determined  through  observation 
of  diuresis,  then  we  must  look  to  the  pre- 
monitory symptoms  which  in  such  cases  us- 
ually occur  after  the  administration  of  salvar- 
san, these  being  coated  tongue,  prostration, 
vomiting,  headache,  a  general  discomfort  due 
to  disturbance  of  the  renal  function,  and  which 
point  to  the  need  for  a  more  exact  investigation 
of  such  symptoms  according  to  the  method  of 
Schlayer  and  Takayasu,  and  then  we  must 
avoid  further  burdening  the  kidneys. 

Generally  speaking  a  determination  of  the 
quantity  of  urine  and  its  specific  gravity,  se- 
cured over  several  days,  suffices,  and  it  is  only 
seldom  that  one  will  be  required  to  employ  the 
more  refined  functional  tests.  It  appears  to 

—  95  — 


8 ALVARS AN     FATALITIES 


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—  96  — 


8ALVARSAN     FATALITIES 

be  of  large  importance  not  to  reach  conclusions 
based  upon  examinations  made  directly  after 
injection  but  rather  to  postpone  judgment  until 
the  second  or  third  day,  especially  if  there  be 
a  moderate  temperature. 

Chart  V  shows  how  a  patient  who  had  re- 
ceived five  injections  of  salicylate  of  mercury, 
presenting  a  polyuria  thereafter,  had  no  change 
in  urinary  secretion  following  an  injection  of 
0.1  salvarsan,  but  who  after  the  second  injec- 
tion of  0.4  salvarsan  presented  a  polyuria  of 
3000  c.cm.  The  next  day  this  dropped  to  a 
normal  quantity,  1700  c.cm.  The  third  injec- 
tion was  responded  to,  not  on  the  same  day 
but  on  the  following  day,  with  a  temperature 
of  39  C.  (102.2  Fahr.)  ;  in  contradistinction 
to  this  rise  of  temperature  the  urinary  secre- 
tion was  about  normal,  1400  c.cm.  The  next 
day  the  temperature  dropped  to  normal.  How- 
ever, on  the  fourth  day  after  the  injection  the 
blood  contained,  according  to  Prof.  Loeb's  es- 
timation, a  strikingly  large  quantity  of  arsenic ; 
the  exact  quantitative  amount  was  not  ascer- 
tained. 

Isolated  cases  of  a  similar  character  have 
been  reported  where  death  took  place  even 
with  normal  diuresis.  The  type  is  as  follows. 
Case  of  Balzer  and  Candat.* 

Male,  34  years  of  age,  two  chancres  on  chin. 
Calomel  ointment  30  per  cent.  One  week  later 
mucous  patches  on  right  tonsil  with  abundant 
spirochaetes.  No  roseola.  Urine  normal.  No- 
vember 24th  0.3  salvarsan  intravenously.  Four 
hours  later  chills,  temperature  39.2  C.  (102.6 
Fahr.).  December  1st  urine  free  from  albumin. 


*Bulletin  de  la  soci£t6  de  dermat.     1912,  No.  1. 
—  97  — 


8ALVAR8AN     FATALITIES 

Salvarsan  0.3.  Temperature  37.6  C.  (99.7  Fahr.). 
December  2nd  anorexia.  December  3rd  unrest, 
delirium,  semi-consciousness,  twitchings,  rigidity. 
Reflexes  retained.  Unequally  dilated  pupils.  Urine 
clear,  in  good  quantity,  without  albumin  or  sugar. 
Coma.  Cerebrospinal  fluid  showed  high  pressure 
and  clear,  few  cells,  marked  quantity  of  albumin, 
positive  Wassermann.  December  4th  cyanosis. 
December  5th  some  albumin  in  urine.  Second 
lumbar  puncture,  abundant  polynuclear  cells. 
Epileptic  attack.  Death.  No  autopsy. 

On  the  same  day  eight  other  patients  were 
given  the  same  dose  in  the  same  manner  but 
without  reaction.  Therefore,  it  cannot  be  said 
that  the  preparation  was  in  the  least  poisonous. 

Arsenic  in  the  spinal  fluid.  A  noticeable 
quantity  of  arsenic  in  blood  taken  from  a  vein. 
This  blood  was  drawn  on  December  4th.  It 
is  thus  shown  that  in  this  instance  there  was  a 
retention  of  arsenic.  Since  the  elimination  of 
fluids  was  normal  but  an  abundance  of  arsenic 
could  be  demonstrated  in  the  blood  even  after 
several  days,  there  then  could  be  present  an 
interstitial  nephritis,  as  a  result  of  which  the 
capacity  for  the  elimination  of  fluids  was  not 
interfered  with,  while  the  power  to  eliminate 
substances  circulating  in  the  blood  and  the 
power  of  concentration  were  impaired.  One 
must  give  heed  to  these  circumstances  in  judg- 
ing the  individual  salvarsan  fatalities,  in  which 
it  may  be  alleged  that  only  salvarsan  was  em- 
ployed. In  all  vascular  nephritides  following 
cessation  of  oliguria  there  comes  a  stage  of 
polyuria  in  which  lactose  elimination  is  more 
or  less  interfered  with ;  often  there  will  be  al- 
most complete  retention  (Schlayer  and  Tak- 
ayasu,  /.  c.,  page  383).  Neither  an  increased 

—  98  — 


SALVAR8AN     FATALITIES 

nor  a  normal  urinary  secretion  permits  a 
definite  conclusion  to  be  reached  of  an  intact 
or  specially  good  function  of  the  kidneys.  Gen- 
erally speaking,  both  represent  a  milder  grade 
of  damage  to  the  renal  vessels  than  the  marked 
oliguria,  yet  either  may  exist  in  the  presence 
of  a  high  grade  damage  of  the  renal  vessels 
(/.  c.  p.  389).  This  polyuria  has  for  a  cause 
a  hypersensitiveness  of  the  renal  circulatory 
system  in  consequence  of  morbid  irritations; 
these  may  be  lasting  or  transitory.  The  same 
sort  of  condition  can  be  caused  by  syphilis. 
Hirsch*  directed  attention  to  the  frequency  of 
contracted  kidneys  of  an  insidious  character 
in  syphilitics.  Lohlein  pointed  out  the  possible 
connection  of  primary  syphilitic  disease  of 
the  blood  vessels  with  this  form.  It  is  quite 
noteworthy  that  the  cases  of  contracted  kid- 
ney without  arteriosclerosis  collected  by 
Roth**  (under  Jorl's  guidance)  mostly  con- 
cerned young  individuals. 

Hirsch  also  emphasizes  how  in  such  cases 
which  are  unable  by  reason  of  renal  insuffi- 
ciency to  eliminate  mercury,  severe  poisoning 
takes  place.  This  also  holds  good  with  sal- 
varsan.  In  a  case  of  Dr.  Gey's  (for  this  I  am 
indebted  to  a  private  communication  from  his 
Excellency,  Ehrlich,  in  which  death  took  place 
two  days  after  one  injection,  there  was  found 
a  marked  interstitial  nephritis  with  extensive 
alterations  in  the  glomeruli  and  fatty  degener- 
ation of  the  uriniferous  tubules  together  with 
beginning  cirrhosis  of  the  liver. 


*VircJiow's  ArcTiiv.  Bd.  77. 
**Med.  KliniTc,  1912,  No.  23. 

—  99  — 


SALVAR8AN     FATALITIES 

In  general,  as  shown  by  complications,  al- 
terations in  the  internal  organs  referable  to  the 
abuse  of  alcohol,  are  strikingly  frequently 
found  at  autopsy;  particularly  chronic  lepto- 
meningitis  is  frequently  found.  In  this  con- 
nection the  old  French  proverb,  "La  Syphilis 
et  I'Alcool  font  mauvais  manage,"  may  per- 
tinently be  quoted. 

It  is  clear  that  insufficiency  of  the  kidneys 
does  not  sufficiently  explain  all  cases  of  sal- 
varsan  fatalities.  But  for  the  most  of  these 
cases  which  are  not  to  be  included  in  this  type, 
arsenic  poisoning  offers  no  explanation,  on  the 
contrary  observation  shows  that  here  the  vari- 
ous clinical  pictures  and  death-causes  are  to 
be  considered  together.  Almost  always  these 
patients  are  individuals  with  definite  insuffi- 
ciency of  various  organs,  demonstrable  before 
injection  of  the  agent  and  demanding  great 
caution  in  every  sort  of  surgical  interference. 
Those  cases  in  which  our  present  methods  of 
examination  do  not  disclose  the  cause  of  death, 
are  but  rarely  met  with.  That  extra-renal  con- 
ditions could  influence  a  retardation  of  salvar- 
san  elimination  is  evident.  To  be  drawn  into 
consideration  are  certain  cardiac  disorders. 

Apparently  salvarsan  does  not  have  a  bad 
influence  on  the  heart,  in  fact  in  heart  dis- 
eases, especially  in  arteriosclerosis,  it  is  us- 
ually well  borne.  As  a  rule  it  has  a  splendid 
effect  on  circulatory  troubles  due  to  syphilis. 
On  the  contrary,  however,  salvarsan  is  always 
a  burden  for  an  overworked,  poorly  balanced 
heart.  This  is  demonstrated  by  the  cases  de- 
scribed by  Martius*  in  which  autopsy  disclosed 

*Abhandlungen  uber  Salvarsan.  Bd.  II.  s.  473. 
—  100  — 


SALVARSAN     FATALITIES 

valvular  insufficiency,  sclerosis  of  the  coronary 
arteries  and  myocarditis.  In  this  connection 
retarded  elimination  often  plays  a  considerable 
part.  Also  hypoplasia  of  the  heart  or  kid- 
neys may  also  cause  the  same.  The  same 
holds  good  in  the  employment  of  salvarsan  in 
the  presence  of  febrile  disorders  and  at  the 
conclusion  of  infectious  diseases  (influenza, 
diphtheria,  scarlet  fever) ,  in  which,  under  cer- 
tain conditions,  extensive  functional  disturb- 
ances, mayhap  demonstrable  only  with  the 
most  exact  methods,  may  be  present. 

Then  the  fever  caused  by  contaminated 
water  might  also  lead  to  the  retention  of  sal- 
varsan ;  the  recent  investigations  of  Schwenke- 
becher,  v.  Hosslin  and  others,  show  that  in 
fever  there  is  salt  retention  in  the  blood.  It 
is  to  be  mentioned,  however,  that  patients  who 
have  been  given  intravenous  injections  of  lac- 
tose and  who  had  fever,  40  C.  (104  Fahr.), 
and  chills,  normally  excreted  the  sugar.  Like- 
wise extra-renal  circumstances  have  no  essen- 
tial bearing  on  the  elimination  of  iodide  of 
potassium.  While,  therefore,  foreign  sub- 
stances are  eliminated  according  to  rather  uni- 
form rules,  the  elimination  of  bodily  sub- 
stances (water,  Nad)  is  variable  and  influenc- 
ed by  numerous  conditions,  both  renal  and  ex- 
trarenal. 

Generally  speaking  the  diseased  brain  toler- 
ates salvarsan  well.  That  in  quite  exceptional 
instances  patients  with  extensive  changes  or 
with  diseased  foci  in  vital  centers,  do  not 
tolerate  the  treatment,  particularly  when  they 
receive  rather  large  doses,  is  not  difficult  to 
understand ;  it  should  be  emphasized,  however, 

—  101  — 


SALVARSAN     FATALITIES 

that  oftentimes  in  such  cases  the  injection  is 
borne  without  reaction,  and  then  frequently 
enough  one  experiences  sudden  deaths  with 
mercury  injections  or  even  without  any  ther- 
apy whatsoever.  Latent  meningeal  tubercu- 
losis appears  to  offer  a  certain  danger  as  sev- 
eral fatal  cases  of  Finger's  show.  It  is  our 
habit  in  tuberculosis  with  headache  always  to 
examine  the  spinal  fluid  before  the  employ- 
ment of  salvarsan  that  it  may  be  clearly  de- 
termined whether  it  is  lues  or  tuberculosis. 

There  yet  remain  to  be  considered  occasional 
fatal  cases  due  to  acute  yellow  atrophy  of  the 
liver.  Such  cases  are  frequently  observed  in 
consequence  of  syphilis  and  the  employment  of 
mercury  as  treatment,  so  one  cannot  attribute 
them  to  the  salvarsan,  particularly  since 
they  as  a  rule  occur  at  a  considerable  period 
after  the  injection;  and  the  less  so  since  just 
here  the  most  surprising  results  of  salvarsan 
(Umber*)  have  been  described  even  after 
failure  of  the  most  active  mercury  prepara- 
tions (Duhot**).  Therefore,  it  is  to  be  con- 
sidered that  acute  yellow  atrophy  of  the  liver 
due  to  florid  syphilis  may  associate  itself  with 
a  severe  epithelial  necrosis  of  the  kidney 
which  is  not  recognized  clinically,  and  offer- 
ing great  difficulties  in  the  way  of  elimination 
of  every  drug  agent,  as  described  by  Janssen 
in  his  Dissertation  (Berlin,  January  14th, 
1911).  Therefore,  the  conclusion  is  that  the 
condition  which  we  have  been  in  the  habit  of 
describing  as  acute  yellow  atrophy  of  the  liver, 

*Abhandlungen  zur  Salvarsantherapie,  Bd.    li, 
s.  365. 

**Ebenda,  s.  352. 

—  102  — 


8ALVAR8AN     FATALITIES 

is  only  the  acute  terminal  process  of  a  clinical- 
ly latent  but  clearly  demonstrable,  chronic 
condition. 

In  this  connection  the  excellent,  searching 
investigations  of  Severin  and  Heinrichsdorf* 
concerning  these  circumstances,  are  to  be  re- 
membered. One  case  especially  of  these  au- 
thors, in  which  icterus  followed  immediately 
the  third  injection  of  salvarsan,  can  accord- 
ing to  my  opinion,  best  be  explained  on  the  as- 
sumption that  the  last  injection  of  the  hither- 
to well  borne  salvarsan,  offered  the  broken  link 
of  a  chain  for  the  causative  factor. 

If  one  takes  into  consideration  the  pre- 
viously reported  salvarsan  fatalities,  then  may 
one  entertain  the  hope  that  in  the  future  sim- 
ilar cases  can  be  avoided  almost  without  ex- 
ception, and  that  but  a  few  not  sufficiently  ex- 
plained, remain  to  be  dealt  with.  Future  in- 
vestigations will  discover  the  genesis  of  these, 
and  it  must  be  endeavored  to  explain  whether 
insufficiency  of  other  organs  plays  a  part  in 
connection  with  these  cases.  One  must  now 
think  especially  of  the  choroidal  plexus.  Our 
case  shows,  as  does  that  of  Balzer,  that  with 
retention  of  salvarsan  in  the  blood  the  choroid 
plexus  may  be  so  badly  damaged  that  the  pre- 
viously albumin-free  liquor  will  contain  an 
abundance  of  albumin,  in  fact,  even  to  the 
point  of  spontaneous  coagulation.  With  the 
normal  choroid  plexus,  injections  of  salvarsan 
cause  no  increase  in  albumin.**  As  to  this 
point  it  must  be  carefully  determined  if  the 

*Zeitschr.  f.  Tclin.  Med.,  Bd.  76,  s.  138. 
**Wechselmann:  Die  Wirkung  des  Salvarsans  auf 
den  Liquor  cerebrospinalis.  Berl.  klin.  Wochenschr., 
1912. 

—  103  — 


SALVARSAN     FATALITIES 

plexus  in  the  case  of  salvarsan  fatalities  under- 
goes pathological  changes.  We  know  that 
with  tuberculosis  the  permeability  of  the  same 
to  certain  substances  is  increased,  and  the 
same  might  occasionally  hold  good  with  syph- 
ilis. 

Schmorl,*  for  instance,  reported  that  a 
quantity  of  substances,  which  are  dissolved  in 
the  blood,  pass  into  the  spinal  fluid  but  not  into 
the  ventricular  fluid,  and  conversely ;  that  in 
both  of  these  fluids  there  may  be  differences 
in  the  content  of  biliary  pigment,  albumin, 
sugar  and  those  substances  which  cause  the 
Wassermann  reaction.  The  normal  inter- 
change of  these  substances  could  also  be  hin- 
dered if  more  or  less  severe  changes  are  pres- 
ent in  the  plexus.  In  this  case  of  Schmorl's 
there  was  a  gummatous  condition  apparent  in 
an  anterior  section  of  the  corpus  callosum. 
Syphilitic  granulation  tissue,  taking  the  place 
of  nervous  tissue,  had  encroached  upon  the  su- 
perior choroidal  horns  and  in  the  tissue  of  the 
plexus  there  were  extensive  small-cell  infiltra- 
tions ;  the.  epithelium,  in  great  part,  was  miss- 
ing. The  blood  and  ventricular  fluid  gave  a 
positive  Wassermann,  the  spinal  fluid  a  nega- 
tive. 

A  recently  published  paper  by  Langbein 
and  Oeller,  a  clinico-pathological  contribution 
to  the  question  of  acute  hemorrhagic  encepha- 
litis (from  the  Leipziger  Institute  of  von 
Strumpell  and  Marchand),  seems  to  me  to 
possess  a  distinct  bearing  on  our  question.  A 
35  year  old  woman,  free  from  signs  of  lues 

*Verhandlungen  der  pathologischen  GesellscTiaft, 
1910,  B.  288. 

—  104  — 


SALVARSAN     FATALITIES 

and  without  demonstrable  infection,  died  with 
clinical  phenomena  of  hemorrhagic  encephali- 
tis, which  was"  confirmed  at  autopsy.  More- 
over, there  were  found  primary  and  secondary 
inflammatory  processes  in  the  meninges  of 
the  base  and  convexity  of  the  cerebrum.  "In 
this  case  it  seems  justifiable  to  conclude  that 
the  other  existing  changes  in  veins  and  brain 
were  consequent  upon  the  inflammatory  pro- 
cesses in  the  horns  of  the  third  ventricle  and 
the  choroid  plexus  of  the  lateral  ventricle  and 
of  the  third  ventricle,  but  which,  however,  one 
had  to  designate  as  primary  processes,  as  in 
other  organs,  and  in  the  cranial  cavity  no  in- 
flammatory focus  could  be  found  from  which 
a  metastatic  involvement  could  have  taken 
place.  Always  hereafter,  with  similar  cases, 
it  would  be  advisable  to  take  into  consideration 
the  possibility  of  tuberculosis,  and  while  the 
latter  might  be  only  in  the  initial  stage,  yet 
in  a  very  short  time  it  could  lead  to  a  tuber- 
culous meningitis  with  resulting  thrombosis." 
After  all  this  we  are  justified  in  saying  that 
salvarsan  per  se  employed  in  normal  persons 
in  the  customary  dosage  is  nontoxic.  Any 
evil  consequence  observed  is  always  due  to 
some  organic  insufficiency,  especially  of  the 
kidneys.  For  this  insufficiency  the  responsible 
factors  are  frequently  mercury,  perhaps  ex- 
ceptionally rare  salvarsan,  and  also  other 
weakening  factors,  such  as  the  influence  of 
syphilis  on  the  blood  vessels  as  well  as  other 
infections  and  intoxications.  If  the  most 
effective  results  are  to  be  secured  from  sal- 
varsan it  is  of  the  greatest  importance  to  care- 

—  105  — 


8ALVAR8AN     FATALITIES 

fully  heed  the   foregoing  points   during  the 
drug's  administration. 

It  is  quite  conceivable  and,  in  fact,  justifi- 
able, that  some  physicians,  following  the  early 
experience  with  the  other  arsenic  compounds, 
were  distrustful  of  salvarsan  from  the  very 
beginning,  and  friends  of  salvarsan,  even 
though  they  had  seen  its  elegant  healing  effect, 
feared  that  the  not  too  well  understood  collat- 
eral effects  might  operate  to  deprive  us  of  the 
advantage  of  this  agent.  But  this  stage  is 
now  passed.  One  should  not  forget  that  the 
same  opposition  arose  against  mercury  at  the 
time  of  its  introduction  as  now  against  sal- 
varsan. Physicians  have  been  too  prone  to 
minimize  its  good  effects,  and  to  place  in  the 
foreground  the  evil  effects  caused  through 
improper  employment.  Let  us  now  remember 
that  from  1580  to  1655  every  teacher  at  Heid- 
elberg had  to  take  an  oath  that  he  would  never 
use  mercury!  It  is  this  divided  condition  of 
opinion  among  physicians  which  permits,  even 
to  the  present,  the  quack  to  thrive  so  well! 
But  the  standpoint  of  those  physicians  who 
recognized  the  value  of  mercury  even  in  early 
days  and  who  through  the  greatest  care,  reduc- 
ed its  evil  effects  to  the  lowest  possible  point, 
at  last  prevailed.  Rightly,  exclaims  the  great 
Botallius :  "Quis  criminabitur  ignem,  unde 
pro  servorum  negligentia  basilica  domini  con- 
sumpta  est!"  The  same  holds  good  for  sal- 
varsan. My  entire  experience  with  more  than 
25,000  injections  forces  me  to  the  inevitable 
conclusion  that  salvarsan  is  much  less  toxic 
than  mercury.  My  department  in  which  sal- 
varsan is  used  almost  exclusively  has  given 

—  106  — 


8ALVAR8AN     FATALITIES 

me  much  less  care  and  trouble  during  the  past 
three  years  than  in  the  previous,  period  when 
mercury  was  employed ;  it  is  certain  that  the 
undesirable  effects  of  salvarsan  with  us  have 
become  much  rarer  and  of  less  importance  as 
we  have  better  learned  to  master  the  technique 
of  its  use,  and  to  employ  a  dosage  adapted  to 
the  individual  case.  The  clinician  always  has 
to  deal  with  ununiform  clinical  material,  and 
in  that  lies  the  main  difficulty  of  properly  em- 
ploying a  remedial  agent  which  has  been  ex- 
perimentally tested  in  a  laboratory.  The  hope 
of  a  cure  for  infections  binds  the  experimental 
worker  and  the  clinician,  but  the  material  upon 
which  they  work  is  radically  different;  there 
the  healthy  animal  with  sound  organs,  here 
the  patient  exhibiting  the  most  varied  devia- 
tions from  normal.  Therefore,  without  the 
systematic,  definitely  planned  aid  of  the  clin- 
ician the  introduction  of  a  chemotherapeutic 
preparation  is  impossible. 

In  conclusion,  I  wish  to  present  a  list  of 
salvarsan  fatalities  which  have  become  known 
to  me.  Should  I  omit  certain  cases  it  is  be- 
cause they  possess  no  value  for  this  table,  as 
it  is  my  purpose  here  to  offer  not  a  statistical 
presentation  of  cases,  but  rather  to  deal  with 
their  genesis.  It  is  somewhat  difficult  to  bring 
these  observations  from  chaos  to  order,  par- 
ticularly so  since  the  greater  number  of  these 
observations  have  been  imperfectly  described. 
These  observations  will  serve  for  the  establish- 
ment of  certain  principles  which  may  be  em- 
ployed in  future  anomalous  cases  of  salvarsan 
therapy ;  in  this  way  it  will  be  easier  to  find  an 
explanation  of  the  question  involved.  I  am 

—  107  — 


8ALTAR8AN     FATALITIES 

taking  into  consideration  only  those  cases  of 
adults,  for  luetic  infants  die  under  such  varied 
circumstances  that  one  can  scarcely  pick  out 
any  special  cause. 

In  the  beginning,  let  it  be  emphasized  that 
with  subcutaneous  and  intramuscular  injec- 
tions of  salvarsan  the  cerebral  type  of  fatal- 
ities has  not  been  observed.  In  these  methods 
of  administration  apparently  there  is  never 
so  severe  a  burden  thrown  on  the  kidney  as  tc 
occasion  renal  failure. 

FATALITIES   FOLLOWING   SUBCUTANEOUS   IN- 
JECTIONS. 

Below  are  given  the  cases  of  death  which 
have  been  reported  as  following  the  use  of 
salvarsan  subcutaneously.  In  all  there  are  six. 
It  will  be  seen  that  a  direct  connection  between 
death  and  the  use  of  salvarsan  can  hardly  be 
established,  as  the  patients  concerned  suf- 
fered from  the  severest  involvements  of  vital 
organs,  and  salvarsan  was  employed  as  a  last 
resort  in  a  bare  hope  of  saving  the  patient's 
life.  Schiele's  case  (No.  3)  which  is  given 
below,  shows  an  intractable,  malignant  syphilis 
in  the  person  of  a  young  girl,  who,  after  a 
temporary  improvement,  died  two  and  a  half 
months  after  the  injection.  One  case  reported 
by  Marcus  I  am  not  considering  at  all,  as  the 
patient  threw  himself  out  of  a  window  a 
month  after  the  injection.  Therefore,  the  sub- 
cutaneous method,  as  I  have  always  main- 
tained, has  not  with  certainty  been  the  cause 
of  a  death.  The  cases  show  different  types. 

— 108  — 


SALVAR8AN      FATALITIES 


1.  Case  of  Ehlers  and  Jorgenson  (Munch,  med. 
Wochenschr,    No.    42,    1911,   p.    2183).      A   40-year- 
old    paralytic.    .Infection    eleven    years    previous. 
Since  1908  symptoms  of  paralysis.     In  June,  1910, 
apopletic   attack.     Since   then   decrease   in   bodily 
weight.     On  Aug.  25th,  1910,  injection  of  0.5  "606" 
subcutaneously.     Thereafter   gradually    increasing 
indications    of   poisoning   of   the   nervous    system. 
Tremor,  outbreaks  of  perspiration,  etc.     Rapid  de- 
cline  in  strength.     Five   days  after  the   injection 
death    took    place    with    symptoms    of    progressive 
paralysis  of  the  heart. 

Autopsy:  Fatty  degeneration  of  the  heart,  kid- 
neys and  liver. 

2.  Case  of  Martius.     (Munch  med.  Wochenschr. 
No.  20,  1911.)     56-year-old  woman  with  cardiac  at- 
tacks.    Aortitis  luetica,  with   insufficiency   of  the 
aortic  valve,  established  clinically.     A  radiogram 
showed  a  diffused  thickening  of  the  aorta  but  no 
aneurism.     In  spite  of  inunctions  the  cardiac  at- 
tacks increased,  for  which  reason  0.5  gram  of  sal- 
varsan     in    neutral    suspension    was    given    sub- 
cutaneously.   At  first  these  attacks  ceased,  but  two 
weeks   later   again    began,   and    on   the   17th   day 
death  took  place  in  an  anginal  attack. 

Autopsy:  Hypertrophy  of  the  left  ventricle, 
aortic  insufficiency,  aortitis  luetica,  hydropericar- 
dium,  hydrothorax,  moderate  interstitial  nephritis. 

3.  Case    of    Schiele.      (St.    Petersburger    med. 
Wochenschr.,  No.  33,  1911.)      29-year-old  girl  with 
congenital   syphilis.     In   spite  of  every  treatment 
the  disease  processes  made  progress.     Poorly  de- 
veloped,   infantile    appearance,    completely    deaf. 
Palace  perforated.    Both  apices  of  lungs  infiltrated, 
liver  and  spleen  enlarged.     Abdominal  pain  upon 
pressure,    finally   hallucinations,    etc.     A   trepana- 
tion wound  of  the  mastoid  process  suppurated  for 
nine  months.     On  Oct.  10th  a  subcutaneous  injec- 
tion of  salvarsan,  0.3  was  given.     Temporary  im- 
provement.    Death   Dec.   26th. 

4.  Case    of    Schiele.      (St.    Petersburger    med. 
Wochenschr.     No.   33,   1911.)      28-year-old   patient 
infected  eight  years  before.    Since  then  irregularly 
treated  with  mercury.     Suffered  from  paralysis  of 

—  109  — 


SALVARSAN      FATALITIES 


the  left  side  of  the  body,  with  disturbances  of 
swallowing  and  speech.  Injection  of  0.4  salvar- 
san  subcutaneously.  Death  in  five  days. 

Autopsy:  Large  soft  focus  in  cerebellum. 
Chronic  leptomeningitis.  Arteriosclerosis  of  the 
basal  arteries. 

5.  Case  of  Spiethoff.     (Munch  med.  Wochenschr., 
No.  4,  1911.)     In  a  patient  suffering  from  gastric 
crises  of  an  indeterminate  nature,  there  was  found 
a  well  compensated,  moderate  aortic  insufficiency. 
Wassermann   positive.     A   careful   x-ray   examina- 
tion disclosed  nothing,     injection  of  0.3  salvarsan 
subcutaneously.     At  first  well  borne.     After  a  few 
days  the   heart  became  weaker  and  weaker,   and 
on  the  llth  day  following  injection,  caused  death. 

Autopsy:  Aortic  insufficiency,  aortitis  luetica, 
myocardial  degeneration,  marked  sclerosis  of  the 
coronary  arteries. 

6.  Case    of    Hans    Willige.       (Muench.    med. 
Wochenschr.    No.   46,   1911,   page   2403.)      Patient 
44  years  old,  infected  with  syphilis  in  1892;    be- 
came a  diabetic  ten  years  later.     Since  1908  had 
disturbances  of  vision.    Wassermann  strongly  posi- 
tive.     Somewhat    emaciated.      Pupillary    reaction 
sluggish.     Vision,  right,   %;   left,  1/10.     Liver  en- 
larged   with    nodular    thickening.      Urine,    daily 
quantity  2  to  2y2  litres  with  2.5  to  3.5  grams  al- 
bumin.    Patient   shows   a   changeable   disposition, 
now  excitable   now  depressed.     On  Sept.  9th,  1910, 
injection    of    0.35    gram    of    salvarsan    given    sub- 
cutaneously between  the  shoulder  blades.    The  fol- 
lowing day  patient  could  sleep,  yet  showed  a  deep, 
painful  infiltration  at  the  site  of  injection.     The 
next   day   there   came   vomiting,   abdominal    pain, 
constant  distress  with  marked  thirst.    At  the  same 
time  an  eruption  appeared  on  the  arms.     On  Sept. 
12th  condition  the  same.     On  the  13th  coma,  pulse 
110,   irregular.     From  the  afternoon   on   patient's 
condition  grew  steadily  worse.     Death  on  the  15th. 

Autopsy:  Cerebral  edema,  myocardial  degenera- 
tion, light  parenchymatous  inflammation  of  the  in- 
testinal tract,  the  liver  and  the  kidneys.  Trace  of 
arsenic  in  the  urine  and  in  the  liver. 

—  110  — 


8ALVAR8AN     FATALITIES 

DEATHS  FOLLOWING  INTRAMUSCULAR  INJEC- 
TIONS. 

Fifteen  deaths  have  been  reported  follow- 
ing intramuscular  injections.  Besides  these 
there  are  two  other  cases  cited  by  Jadassohn, 
in  which  it  could  not  be  clearly  determined 
whether  the  injection  had  been  given  intra- 
muscularly or  subcutaneously.  Also  in  these 
cases  there  could  not  be  shown  any  connection 
between  the  salvarsan  and  death,  that  is,  in 
the  sense  of  a  poisoning.  In  a  few  cases  death 
follows  a  month  or  more  later  from  septicemia 
or  hemorrhage.  Comparatively  speaking  em- 
boli  often  follow  this  method,  in  contradis- 
tinction to  their  non-occurrence  in  the  sub- 
cutaneous method. 

1.  Case  of  Dr.  A.  in  K.   (Martius).     (Muench. 
med.  Wochenschr.,  No.  20,  1911.)     Patient  47  years 
old,  tabetic,  suffering  with  aortitis  and  aneurism 
of    the    arch.      Wassermann    positive.      Upon    ex- 
pressed wish  of  patient  0.6  gram  of  salvarsan  in- 
jected intragluteally.     Following  this  with  entire 
loss  of  appetite  patient  became  weaker  and  weaker. 
Fifteen  days  after  injection  there  appeared  a  pain- 
ful,  hemorrhagic  pemphigus.     Death   on   the  21st 
day. 

Autopsy:  Hypertrophy  and  dilatation  of  the  left 
ventricle,  and  moderate  dilatation  of  the  arch  of 
the  aorta.  Atrophic  liver  showing  fatty  degenera- 
tion. Marked  parenchymatous  degeneration  of  the 
kidneys. 

2.  Case    of    Finger    (Mucha).      (Wiener    klin. 
Wochenschr.,  No.  27,  1911,  page  963,  and  No.  28, 
1911,  page  1012.)     Child,  seven  years  old,  well  de- 
veloped, with  mucous  patches  on  lips  and  papules 
on  the  genitals.    Eyes  normal.    Chronic  middle  ear 
trouble   (suppuration).     Light  bronchitis;      no  al- 
bumin.    Jan.   17th  intramuscular  injection  of  0.2 
gram    salvarsan.      Following    day,    headache    and 

—  111  — 


8ALVAR8AN      FATALITIES 


Herxheimer  reaction.  Papules  showing  improve- 
ment; on  following  day  cured.  On  Feb.  18th  in- 
voluntary movements  of  the  head  and  eyes.  On 
Mar  18th,  notwithstanding  that  the  involuntary 
movements  have  ceased,  patient  is  fully  apathetic. 
Vomiting  and  headache..  Lumbar  puncture  shows 
high  pressure,  a  clear  liquid  containing  mono-  and 
polynuclear  leucocytes.  The  previously  strongly 
positive  Wassermann  now  became  weakly  positive. 
On  March  26th,  coma  with  purulent  discharge  from 
the  ear,  which  makes  one  suspect  an  abscess  of 
the  brain.  March  31st,  trepanation  was  tried  but 
without  results.  April  3rd,  patient  died. 

Autopsy:  Purulent  leptomeningitis  of  the  base. 
Increase  of  ventricular  fluid.  Tuberculosis,  cal- 
culous  nodules  of  the  spleen. 

3.  Case  of  Herxheimer  and  Altmann.     (Deutsche 
med.  Wochenschr..  No.  10,  1911.)     Male,  25  years 
old,    with    symptoms    of   a    progressive    paralysis. 
Several  years  ago  apical  tuberculosis.    Intragluteal 
injection  of  0.5  gram  salvarsan  in  neutral  solution 
Sept.  15th,  1910.    On  the  20th  one  can  see  a  marked 
infiltration  at  the  site  of  injection.     Patient  com- 
plains of  sharp  cough  with  slimy   material   from 
bronchi.      Died  suddenly  on  Oct.  5th  of  pulmonary 
embolism  following  a  thrombus  from  the  femoral 
vein,  which  was  due  to  a  streptococcus  infection 
at  the  point   of  injection. 

Autopsy:  Old  fibrous  deposit  in  both  apices,  and 
encysted  caseous  foci.  Peural  adhesions. 

4.  Case  'of  Hrdliczka.      (Wiener  Jclin.  Wochen- 
schr., No.  21,  1911.)     Officer,  33  years  old,  infected 
1903.     From  then  to  1908  well  treated  with  mer- 
cury.   Since  1909  increase  of  symptoms.    Oct.  24th, 
1910,  intramuscular  injection  of  0.6  gram  of  sal- 
varsan in  neutral  suspension.     At  the  time  there 
was  a  periostitis  of  the  tibia.    With  January  came 
stomach   disturbances,   vomiting,   attacks   of   dizzi- 
ness, and  disturbances  of  vision.    On  February  6th, 
noticed  weakness  of  memory.     Wassermann  nega- 
tive.   Clinically  there  is  nothing  to  be  seen,  neither 
of  nervous  nor  organic  ailments.     February  28th 
came   stiffness   of   jaws,    facial   paralysis,   disturb- 
ances of  speech,  fever  and  unconsciousness.     Pa- 
tient  died   March   8th. 

—  112  — 


SAL VAR8 AN      FATALITIES 


5.  Case  of  Jacquet.     (Gazette  des  Hop.,  No.  120, 
1911.)     Patient  42  years  old,  alcoholic,  with  ulcer- 
ated syphilide  the  size  of  a  dollar  on  thigh.     For 
years    patient    has    complained    of    vomiting    and 
bowel   disturbances,   due  presumably  to   dilatation 
of  the  stomach,      t>ept.    17th   intramuscular   injec- 
tion of  0.5  gram  salvarsan.     Pronounced  pain  and 
moderate    fever.      The    syphilide    cleared    up    and 
healed   over.     On   the   seventh   day   following   the 
injection     patient     vomited     dark     masses.       The 
anemia  and  weakness  increased.     Death  Sept.  29th. 

Autopsy:  Ulcus  ventriculi  with  rough  edges, 
pyloric  stenosis,  dilatation  of  the  stomach. 

6.  Case  of  Lane.      (Bri.  Med.  Jour.,  Sept.  23rd, 
1911,  page  673.)     Patient  27  years  old,  infected  six 
months    previously.       At    the    time    of    injection 
phagedenic   ulcer    on   penis,    ulcerations    upon   the 
inner  side  of  the  thigh  and  palate.     Six  calomel 
injections   without   any   result.      Sept.    24th    intra- 
muscular  injection   of   0.5    gram    salvarsan.      Not- 
withstanding the  injection  the  palate  perforated; 
the   completely   necrotic   jaw-bone    had    to   be   re- 
moved.    Death  occurred  bee.  2nd  from  septicemia. 

7.  Case   of   Martius.      (Muench.    med.   Wochen- 
schr.,  No.  20,  1911.)     Patient  with  tabes.     Clinical 
examination  of  the  heart  discloses  an  accentuated 
second   aortic   sound.      Intramuscular   injection   of 
0.6  gram  salvarsan  in  8  c.cm.  olive  oil.    Well  borne. 
Girdle  pains  disappeared.    On  the  sixth  day  follow- 
ing injection  death  suddenly  occurred. 

Autopsy:  Syphilitic  aortitis.  Moderate  sclerosis 
of  the  aorta  and  ihe  peripheral  arteries.  Moderate 
dilatation  and  hypertrophy  of  the  left  ventricle. 
Fresh  foci  of  degeneration  in  the  heart  muscle, 
particularly  in  the  left  ventricle. 

8.  Case   of   Martius.      (Muench.    med.   Wochen- 
schr.,  No.  20,  1911.)     Paralytic,  47  years  old,  with 
lung    tuberculosis.      Intragluteal    injection    of    0.5 
gram  salvarsan  in  neutral  suspension.     Two  weeks 
later  death  occurred  from  pulmonary  emboli   fol- 
lowing necrosis  at  site  of  injection. 

Autopsy:     Confirmation  of  clinical  findings. 

9.  Case    of    Schiele.       (St.    Petersburger    med. 
Wochenschr.,    No.    33,    1911.)       Twelve    year    old 
scholar.      Malignant    syphilis.      Great    damage    to 

—  113  — 


8ALVAR8AN      FATALITIES 


bony  parts  of  nasal  passages;  almost  all  of  the 
soft  palate  is  destroyed.  The  hard  palate  covered 
with  deep  ulcerations.  Intramuscular  injection  of 
0.3  gram  salvarsan.  Following  injection  patient  is 
very  restless.  Temperature  rises  to  between  38  and 
40  C.  (100.5 — 104).  Ulcerations  respond  slowly. 
For  this  reason  mercurial  course  is  given.  After 
six  weeks  an  injection  of  0.5  gram,  salvarsan  is 
given;  necrosis  at  the  site  of  the  injection  gives 
rise  to  a  fatal  hemorrhage. 

10.  Case  of  Spiethoff.     (Muench.  med.  Wochen- 
schr.,    No.    4,    1911.)      Female,    28    years    of    age, 
markedly    cachetic,    tertiary    lues    of    the    palate. 
Treated    without    results    with    atoxyl    for    three 
years.     An   intramuscular   injection   of   0.5    gram 
salvarsan   given   on   the  afternoon   of   June   20th. 
At  ten  o'clock  in  the  evening  no  visible  changes; 
slight    pain   at   sight    of    injection    required    mor- 
phine.    At  five  o'clock  next  morning  the  woman 
was   found   dead   in   bed. 

Autopsy:  Tertiary  syphilis  of  the  palate,  cica- 
tricial  stricture  of  the  pharynx,  gummatous  scar 
in  liver,  hyperplasia  of  the  heart  and  of  the  aorta. 
No  trace  of  arsenical  poisoning. 

11.  Case  of  Werther.     (Muench.  med.  Wochen- 
schr.,  No.  10,  1911,  page  505.)     Sixty-year-old  man, 
very  anemic,  suffering  from  cerebral  syphilis  and 
hemiplegia.     Intramuscular  injection  of  0.5  gram, 
salvarsan.     Death  following  day. 

Autopsy:  Large  soft  focus  in  brain.  Endar- 
teritis  of  the  cerebral  arteries,  syphilitic  aortitis, 
myocardial  degeneration. 

12.  Case  of  Westphal.     (Berliner  klin.  Wochen- 
schr.,  No.   22,  1911,  page  973.)      Woman   33  years 
old,    alleges   no    infection    yet   three    miscarriages 
have   occurred.      (At   an   earlier   period   the   hus- 
band   had    had    a    chancre.)      Never    treated    for 
syphilis.     Complained  of  lancinating  pains,  dizzy 
spells,   difficulty  of  hearing,  vomiting  and   double 
vision.     Gradually   locomotion   became   disturbed; 
after    six    months    complete    loss    of    locomotion. 
Then  paralysis  of  arms.     Clinical  examination  on 
June  22,  1911,  discloses  loss  of  pupillary  and  pa- 
tellar  reflexes.     July  14th  received  an  intragluteal 
injection   of   0.2    gram   salvarsan   in   neutral   sus- 

—  114  — 


S ALVARSAN      FATALITIES 


pension.  At  first  well  borne.  Shortly  afterwards 
complains  of  dyspnea,  which  in  spite  of  artificial 
respiration  quickly  progresses  to  apnea.  Death  36 
hours  later. 

Autopsy:  Syphilitic  aortitis.  -Degeneration  of 
the  posterior  columns,  and  acute  specific  spinal 
meningitis. 

13.  Case  of  Willige.      (Muench.   med.   Wochen- 
schr.,  No.   46,  1910,  page  2403.)      Following  intra- 
muscular injection  of  0.8  gram  salvarsan  appeared 
rather  severe  phenomena.    At  the  site  of  injection 
there   was   visible   a  dark,   hemorrhagic    eruption, 
which  quickly  spread  to  the  buttocks  and  thighs, 
and  only  cleared  up  after  five  days  and  then  with 
scar    formation.      Wassermann    became    negative 
after  four  weeks.     Appearance  of  an  eruption  re- 
sembling acne.     At  the  site  of  injection  one  could 
note   a   painless   infiltration.     Death   seven   weeks 
after  injection  in  consequence  of  a  fresh  paralytic 
attack. 

14.  Case     of     Jadassohn.        (Deutsche     med. 
Wochenschr.,  No.  51,  1910.)     Forty-year-old  patient 
in  bad  general  condition.     No  history  of  syphilis. 
Aortic    aneurism    with    much    pain.      Injection    of 
0.4  gram  salvarsan.     At  first  mild  rise  in  tempera- 
ture, then  drop  to  normal.    On  the  ninth  day  after 
injection   death  took  place. 

Autopsy:  Aortic  aneurysm,  spleen  and  kidney 
infarcts,  pneumonia,  left  lower  lobe. 

15.  Case     of     Jadassohn.        (Deutsche     med. 
Wochenschr.,    No.    51,    1910.)      Forty-year-old    pa- 
tient with  severe  cerebral  syphilis,   marked   myo- 
carditis,   weakness    of    heart.     At    request   of    the 
mother  of  patient,  an  injection  of  0.1  of  salvarsan 
was   given   notwithstanding   that   patient   was   al- 
ready in  extremis.     Death  on  following  day. 


DEATH  AFTER  INTRAVENOUS  INJECTIONS. 

And  now  will  be  reported  these  fatalities 
taking  place  after  intravenous  injections  of 
salvarsan,  which  occurred  shortly  after  the  in- 
jection, and  in  which  plain  technical  errors  or 

—  115  — 


SALVARSAN      FATALITIES 

organic  changes  might  be  held  responsible  for 
the  death.  It  is  evident  that  doses  far  in  ex- 
cess of  what  the  patient's  condition  warranted, 
were  employed. 

Generally  speaking  it  is  highly  probable  that 
fatalities  which  occur  in  a  short  time,  even 
within  a  few  hours,  after  the  injection  can 
take  place  as  a  result  of  unnoticed  errors. 
Pointing  to  this  is  the  circumstance  that  they 
are  rarely  reported,  and  practically  never  by 
physicians  who  have  given  many  injections. 
To  forget  to  render  the  salvarsan  solution 
alkaline  is  especially  dangerous  if  the  solution 
is  not  very  much  diluted.  Another  dangerous 
factor  is  the  non-detection  of  the  so-called 
"anaphylactic"  state,  for  the  introduction  of  a 
large  quantity  of  salvarsan,  during  such  a 
state,  could  easily  be  the  cause  of  death.  It 
is  noteworthy  that  these  cases,  once  all  too 
frequently  reported,  now,  since  the  employ- 
ment of  the  intravenous  method  of  adminis- 
tration, are  but  rarely  recorded.  Either 
these  cases  have  been  preventable  cases  or  the 
fatalities  have  been  due  to  lesions  which  were 
very  severe  within  themselves. 


1.  Case  of  Paul  Bar.     (Bull,  de  I'Acad.  de 

No.  55,  1911.)  Nineteen  days  after  receiving  an 
intravenous  injection  of  0.5  gram  of  salvarsan,  dis- 
solved in  100  c.cm.,  a  pregnant  woman  showed  a 
marked  albuminuria.  Shortly  thereafter  an  an- 
gina. The  patient  was  delivered  of  a  dead  child. 
Died  five  days  later  of  a  double-sided  pneumonia. 

2.  Case    of    Dind.     An    old    man,    addicted    to 
tobacco  and  alcohol,  in  poorly  nourished  condition, 
circulatory    disturbances,     markedly     tuberculous. 
Died  three  days  after  the  injection  with  pulmonary 
symptoms  and  renal  suppuration.     (Dose  and  skill 
unknown.) 

—  116  — 


SALVARSAN      FATALITIES 


3.  Case  of  Dind.     An  old  syphilitic.     Reached 
hospital  in   coma  and   was   given   an   injection   of 
0.1  gram  salvarsan  as  a  last  resort.     Died  during 
afternoon. 

Autopsy:  Tuberculous  meningitis,  pulmonary 
tuoerculosis. 

4.  Case  of  De  Favente.     (Giorn.  ital.  delle  mal. 
ven.  e  delle  pelle,  1912.)     Patient  31  years  old;  in- 
fected  ten   years   before.      Patient   received    three 
calomel     injections.       Wassermann    still    positive. 
Patient  complained  especially  of  severe  headache 
at  night.     Intravenous  injection  of  0.48  gram  sal- 
varsan.    Two   hours   after   injection   unconscious, 
epileptic  attack  lasting  an  hour  and  a  half,  with 
conapse.     Death  ten  hours  after  the  injection. 

Autopsy:  Syphilitic  basal  meningitis,  diffuse 
gummata  of  the  liver,  cerebral  hemorrhage. 

5.  Case    of    Finger    (Mucha).      (Wiener    klin. 
Wochenschr.,    Nos.    27-28,    1911.)      Male,    33    years 
old,  with  secondary  syphilis.     (Iritis  and  neuritis 
optica.)     Ears  and  internal  organs  healthy.     Jan 
hrd,   0.4    gram   salvarsan    intravenously.     Wasser- 
mann  ++.     On  following  day  Herxheimer  reac- 
tion.   On  the  14th  gone.    Wassermann  +.    Second 
injection  of  0.4  gram  well  borne.     Jan.  31st  Was- 
sermann +  +  •    March  9th  recurrence  with  neuritis 
optica   hemorrhagica.     March    13th   no   particular 
nervous  symptoms.     On  the  following  day  patient 
complained  of  severe  pain  in  the  ears;   headache, 
and     indisposition.       March     15th    another    intra- 
venous injection  of  0.4  gram.     The  following  day 
patient  suffered  from  headache  and  vomiting,  but 
on  the  17th  entirely  well.     March  18th  patient  had 
a  double-sided  paralysis  of  the  lower  extremities 
with  a  Babinski.     March  23rd  right-sided  paralysis 
of   the   face.     On   the   25th   left-sided   hemiplegia. 
On  the  following  day,  clonic  convulsions  and  fever. 
Marcn  28th,  death. 

Autopsy:  Acute  tuberculosis  of  base  of  brain, 
kidneys  and  intestines.  Chronic  tuberculosis  of 
the  bronchial  and  cervical  glands. 

6.  Case    of    Finger    (Mucha).      (Wiener    klin. 
Wochenschr.,  Nos.   27  and  28,  1911.)      Woman,   22 
years   old,   poorly   developed.     Infected  ten   weeks 
before.     Has  eruption  on  buttocks,  neck  and  the 

—  117  — 


SALVARSAN      FATALITIES 


extremities.  Wassermann  ++.  No  albumin.  In- 
ternal organs  sound.  On  March  29th  given  0.4 
gram  "606,"  following  which  patient  had  headache 
and  light  fever.  Notwithstanding  headache  which 
persisted  patient  received  another  injection  of  0.4 
gram  on  April  llth.  Wassermann  +.  The  fol- 
lowing day  patient  complained  of  general  indis- 
position, diarrhea  and  increased  headache.  Cn 
the  14th  temperature  39  C.  (102  Fahr.).  A  week 
later  patient  fell  into  a  coma.  Lumbar  puncture, 
high  pressure  of  fluid  which  contained  many  lym- 
phocytes, few  polynuclear  leucocytes  and  few  bac- 
teria. Stiffness  of  neck  together  with  eye  and  fas- 
cial  paralysis.  April  27th,  death. 

Autopsy:  Acute  miliary  tuberculosis  of  the  base 
of  the  brain  and  left  lung.  Caseated  bronchial 
glands.  Cerebral  edema,  parenchymatous  degenera- 
tion of  the  heart,  the  liver  and  kidneys.  Acute 
endometritis. 

7.  Case  of  Finger  (Mucha).  (Wiener  klin. 
Wochenschr.,  Nos.  27  and  28,  1911.)  Male,  33  years 
old,  infected  three  months  previously.  At  first 
treated  with  injections  of  mercury.  Jan.  2,  1911, 
reseola  on  buttocks  and  the  extremities.  Wasser- 
mann  +  ++.  Eyes,  ears  and  internal  organs 
sound.  No  albuminuria.  Jan.  7th,  intravenous 
injection  of  0.4  gram  salvarsan.  Well  borne. 
Temperature  39.2  C.  (102  Fahr.).  Jan.  2nd,  second 
injection  of  0.4  gram.  Also  well  borne.  Wasser- 
mann +  ++.  On  Feb.  25th,  patient  presented 
himself  with  severe  iridocyclitis  of  the  right  eye. 
Wassermann  -f.  On  March  3rd,  neuritis  of  the 
vestibular  nerve.  On  March  7th, — 45  days  after 
the  injection — the  urine  still  contained  a  trace  of 
arsenic.  On  March  9th  patient  received  third  in- 
jection of  0.4  gram.  Wassermann  negative.  Only 
headache.  The  vestibular  neuritis  showed  improve- 
ment, yet  the  general  condition  of  the  patient 
steadily  grew  worse.  Dizzy  spells  and  headache 
until  May  15th.  On  the  night  of  this  day  an 
apoplectic  attack  with  right-sided  paralysis  and 
bilateral  neuritis  optica.  Lumbar  puncture,  no 
force,  supplied  about  25  c.cm.  of  a  clear  fluid  which 
contained  many  mono-  and  polynuclear  leucocytes, 

—  118  — 


SALVAR8AN      FATALITIES 


but  no  bacteria.     Patient  died  on  the  same  day  in 
the  evening,  five  weeks  after  last  injection. 

Autopsy:  Fresh  softening  of  the  cerebral  cor- 
tex. Leptomeningitis  of  the  base-  of  the  brain. 
Thrombosis  of  the  vessels  on  the  convexity.  Men- 
inigitis  and  endarteritis  luetica.  Cicatrization  of 
right  lung  with  caseous  foci  in  apices. 

8.  Case  of  Praenkel.      (Muench.  med.  Wochen- 
schr.,  No.  34,  1910,  page  1771.)     Man,  25  years  old, 
confused  speech,  deafness.     Infected  several  years 
before.     Aug.  5th,  injection  of  0.4  gram  salvarsan 
intravenously  in  115  c.cm.  of  water.     Fifteen  min- 
utes later  symptoms  of  arsenical  poisoning.    Death 
in  three  hours. 

Autopsy:  Chronic  leptomeningitis,  heart  weak- 
ness, hypoplasia  of  the  kidneys,  hyperemia  of  the 
liver,  arsenic  in  large  quantities  in  the  spleen, 
lungs  and  liver. 

9.  Case  of  Hoffman.      (Muencfi.  med.  Wochen- 
schr.,  No.   4,   1912.)      Man,   42   years   old,   infected 
five   and   one-half  years   before,   since  then   three 
courses  of  mercury  and  iodide  of  potassium.     At 
this  time  patient  suffered  from  loss  of  sensibility 
in   left   leg,   loss   of  locomotion,   and   difficulty   of 
urination.    Urine  free  of  morbid  elements.    Lumbar 
puncture    shows    a    cloudy,    bloody-tinged    liquor, 
with  considerable  force.     March  3rd,   1911,  intra- 
venous injection  of  0.6  gram  salvarsan.     After  in- 
jection chills,  vomiting,  and  rise  of  temperature  to 
39.7  C.    (103.5  Fahr.).     Next  day  left-sided  fascial 
paralysis.     The  condition  remained  without  note- 
worthy change  until  March  12th,  when  with  slowly 
rising    temperature    and    symptoms    of    increasing 
heart  weakness  death  took  place,  nine  days  after 
the  injection. 

Autopsy:  Sclerosis  of  the  basilar  artery.  Brown 
atrophy  of  the  heart  and  liver.  Gumma  of  the 
spinal  cord  with  degeneration  of  the  posterior  col- 
umns. Chronic  luetic  leptomeningitis. 

10.  Case    of    Klingmueller.       (Muench.     med. 
Wochenschr.,  No.  20,  1911.)     Woman,  26  years  old, 
in  good  health,  complained  of  an  occasional  stick- 
ing pain  in  region  of  the  heart.     Careful  clinical 
examination   together   with   X-ray   inspection   dis- 
closed  nothing.     Patient   knew   nothing   of   luetic 

—  119  — 


SALVARSAN      FATALITIES 


infection  yet  had  two  miscarriages.  Wassermann 
+  ++.  Injection  intravenously  of  0.3  gram  salvar- 
san.  At  first  well  borne.  Despite  physician's  ad- 
vice, the  woman  worked  in  garden  on  the  same 
day  she  received  injection.  She  died  three  days 
later  with  evidences  of  increasing  heart  weakness. 
Autopsy:  Embolus  in  pulmonary  artery,  luetic 
aortitis,  myocardial  degeneration. 

11.  Case  of  Kobler.     (Gesellschaft  fuer  Innere 
Medizin  und  Kinderheilkunde  in  Wien,  Nov.  3rd, 
1910.)     Death  as  a  consequence  of  rupture  of  an 
aortic  aneurysm  not  previously  known. 

12.  Case  of  Dr.  v.  K.  in  S.  (Martius).     (Muench. 
med.  Wochenschr.,  No.  20,  1911.)     A  case  of  aortitis 
syphilitica  which  died  during  the  administration 
of    salvarsan.      Autopsy    disclosed    an    extensive 
aortitis  luetica,  and  a  ruptured  aneurysm  or  the 
thoracic  aorta  just  above  the  diaphragm. 

13.  Case   of  Lane.      (British  Medical  Journal, 
Sept.  23,  1911.)     Male,  30  years  of  age,  apparently 
in  good  health.     Infected  in  1909.    At  the  time  of 
examination  without  manifestations.    Wassermann 
+.     Treated  with  mercury.     Since  patient  contem- 
plated marriage,  he  requested  that  an  injection  of 
salvarsan   be   given   him.     He   received   0.6   gram 
intravenously.      Immediately    after    the    injection 
prostration,  in  the  afternoon  pain  in  breast,  ayspnea 
and     cyanosis.       Pulse     and     temperature     good. 
Through    employment    of    stimulants    patient    re- 
stored.    During  night  died  suddenly. 

14.  Case  from  Mainz.     (Ehrlich's  Discussion  of 
Salvarsan,  11  vol.,   page  576.)      Strong  man.     In- 
fected in  1910.     In  Sept.,  1910,  received  an  intra- 
muscular injection  of  salvarsan.     In  August,  1912, 
on   account   of   small   papular   syphilitic   eruption 
patient  received  0.5  gram  salvarsan  intravenously. 
In   a  snort  time  fever  of  38.6   C.    (101.5   Fahr.), 
vomiting,   liquid   stools;    three   hours   and   a   half 
after  the  injection  death  occurred. 

Autopsy:     Nothing   to   account   for   the   sudden 
death. 

15.  Case  of  Markus.      (Muench.  med.  Wochen- 
schr.,  Jan.  10th,  1911.)     Paralytic,  infected  20  years 
before.     Aug.  26,  1910,  received  intravenous  injec- 
tion  of   0.4   gram   salvarsan.     At  first   there  was 

—  120  — 


8  A L V A R 8  A N      FATALITIES 


improvement,  then  new  attacks  and  finally  death 
by  cerebral  apoplexy  two  months  after  the  injec- 
tion. 

16.  Case  of  Martius.      (Muench.  med.  Wochen- 
schr.,  No.  20,  1911.)      Male,  39  year's  of  age,  with 
cerebral  syphilis.     Heart  trouble  since  1910.     Clin- 
ically,   an    aortic    insufficiency   with    compensation 
could  be  established.     Intravenous  injection  of  0.5 
gram  salvarsan.     Immediately  thereafter  indisposi- 
tion   and    vomiting.      Death    five    hours    later    in 
coma. 

Autopsy:  Marked  hypertrophy  of  both  ventricles, 
high-grade  aortic  insufficiency,  aortitis  syphilitica, 
diffuse  myocarditis.  Degeneration  and  necrosis  of 
urinary  tubules  of  both  kidneys. 

17.  Case  of  Milian.     (Soc.  med.  des  H6p.    Meet- 
ing, Nov.  24,  1911.)     Male,  60  years  of  age,  obese, 
with  unilateral  paralysis  and  mitral  insufficiency. 
Upon  the  express  wish  of  the  patient  he  was  given 
an  injection  of  0.3  gram  salvarsan.     Thirty  min- 
utes  after  injection   patient  fell   into  coma,   with 
rise  of  temperature.     Death  36  hours  later. 

Autopsy:  Acute  edema  of  the  brain.  Dilatation 
of  both  ventricles. 

18.  Case  of  Dr.  B.  in  B.   (Martius).     (Muench. 
med.  Wochenschr.,  No.  20,  1911.)     Male,  35,  strong, 
with   pronounced    paralysis.      One-half   hour   after 
injection,  while  still  in  the  physician's  office,  pa- 
tient suffered  from  a  severe  attack  of  heart  failure. 
With  caffeine  and  ether  patient  was  restored.    Four 
hours   after  the   injection — in   the  meanwhile   the 
patient  had  been  carried  to  his  hotel — death  came 
with  symptoms  of  increasing  weakness  of  the  heart 
muscle. 

Autopsy:  Hypertrophy  of  the  heart,  nephritis, 
cirrhosis  of  the  liver,  cerebral  hemorrhage,  arterio- 
sclerosis. 

19.  Case  of  Plehn.    (Deutsche  med.  Wochenschr., 
No.  2,  1911.)     Male,  49  years  of  age,  afflicted  with 
cerebro-spinal  syphilis  since  July,  1910.     Previous 
treatment  given  elsewhere.     Oct.  1st,  symptoms  of 
a  paralysis  of  the  legs,  bladder  and  bowels.     Dis- 
turbances of  speech  and  mentality.     Cystitis,  con- 
vulsions.   In  spite  of  cachexia,  bed-sores,  and  weak 

—  121  — 


SALVARSAN      FATALITIES 


pulse  an  injection  of  0.5  gram  salvarsan  was  given 
on  Oct.  3rd.     Death  occurred  next  day. 

Autopsy:  Almost  complete  destruction  of  both 
kidneys  by  purulent  processes. 

20.  Case  of  Ravauc.      (Soc.   de  Dermatolog.  et 
Syphil.,  June  1st,  1911.)      Male,  45  years  of  age. 
At  time  of  examination  had  cancer  of  tongue.  Pre- 
sents picture  of  a  very  weak  man.     March  13th, 
1911,  patient  received  intravenous  injection  of  0.6 
gram  salvarsan.     Well  borne.     On  the  20th,  a  like 
dose.     Fifteen  days  later  patient  died  with  symp- 
toms of  progressive  cachexia. 

Autopsy:  Extensive  cancer  of  the  tongue.  Noth- 
ing to  show  arsenical  poisoning. 

21.  Case    of    Schottmueller.       (Muench.    med. 
Wochenschr.,   No.   51,   1910.)      Patient  complained 
of  severe   painful   tumor   in   the   right   upper   ab- 
dominal quadrant.     Upon  exploratory  laparotomy 
it  was  determined  that  the  condition  was  due  to 
syphilis   of   the   liver.     Wassermann    +.     Patient 
received  0.8  gram  salvarsan  in  100  c.cm.  acid  solu- 
tion intravenously.    At  first  well  borne.    The  next 
day,  18  hours  following  injection,  the  patient  died 
suddenly  with  symptoms  of  dyspnea  and  pulmonary 
edema. 

Autopsy:  Gummata  of  the  liver.  Slight  inter- 
stitial nephritis. 

22.  Case  of  Stern.    This  case  reported  by  Stern 
to  the  Congress  of  German  Physicians  in  Karlsruhe, 
bept,  1911,  as  following  the  use  of  a  hyperalkaline 
solution  of  salvarsan. 

23.  Case  of  Treupel.     (Deutsche  med.  Wochen- 
schr.,  No.   23,   1911.)      Inveterate  smoker,   treated 
with  mercury  and   iodide  of  potash  without  any 
results.      Patient    received    two    injections    intra- 
venously of  0.4  gram  each.     Two  days  after  the 
last  injection  patient  manifested  great  cerebral  ex- 
citement, dying  shortly  after. 

Autopsy:  Well  advanced  degeneration  of  the 
posterior  columns.  Diffuse  hemorrhagic  pachy- 
meningitis,  with  fresh  hemorrhages  and  puncti- 
form  hemorrhages  in  the  medulla.  Aortitis  syph- 
ilitica. 

24.  Case  of  Voerner.     (Monatshefte  fuer  prakt. 
Dermatolog.,  Bd.  53,  No.  2,  1911.)    Poorly  nourished 

—  122  — 


SALVARSAN      FATALITIES 


smoker.  Infected  twenty  years  before.  Internal 
organs  without  demonstrable  lesions.  Following 
request  of  patient  given  intravenous  injection  of 
0.6  gram  salvarsan.  After  the  injection  patient 
suffered  from  chills,  headache,  and  vomiting.  The 
next  week  the  patient  was  again  sick  with  vomit- 
ing. In  urine,  one  percent,  of  albumin.  Six  weeks 
later,  after  a  temporary  improvement,  patient  again 
in  bad  condition.  Again  prostrated,  with  diarrhea 
and  complete  apathy.  Spleen  and  liver  swollen. 
Death. 

Autopsy:  Tuberculous  foci  throughout  periton- 
eum. Also  in  spleen,  liver  and  bowels.  Swollen 
tuberculous  glands  in  mediastinum.  Adhesions  in 
both  pleural  cavities. 

25.  Case  of  Queyrat.  (Bull,  de  la  Soc.  franc,  de 
Dermatolog.  et  de  Syphil.,  No.  1,  1912.)  Male,  24 
years  of  age,  chancre  for  ten  days.  Oct.  21st,  0.6 
gram  of  salvarsan  injected  intravenously.  Urine 
free.  Internal  organs  without  abnormal  findings. 
Injection  caused  no  trouble.  No  headache.  How- 
ever, one-half  hour  later  patient  suddenly  seized 
with  prostration.  Unconscious  and  stertorous 
breathing.  In  spite  of  ether  injections  and  artificial 
respiration  patient  died  in  five  minutes. 

Autopsy:  In  the  right  kidney,  on  the  forward 
inner  surface  is  a  broad  effusion  of  blood,  of  the 
size  of  a  fifty-cent  piece.  The  entire  organ  has 
sustained  severe  hemorrhages.  Microscopically  in 
the  glomerulus,  between  the  straight  and  convoluted 
tubules,  are  to  be  seen  widely  dilated  vessels.  The 
epithelium  of  the  convoluted  tubules  is  detached; 
the  lumen  of  the  tubules  in  places  entirely  ob- 
literated. The  damage  seems  to  be  a  diffuse,  acute 
nephritis. 

In  the  following  cases,  by  reason  of  organs 
damaged  by  chronic  alcoholism,  syphilis  or 
mercury,  the  system  was  unable  to  normally 
eliminate  the  administered  salvarsan.  The 
greater  number  of  these  cases  were  given  the 
combined  treatment.  In  Almkuist's  case  (No. 
1)  there  was,  indeed,  an  interval  of  four 

—  123  — 


SALVARS AN      FATALITIES 

months  between  the  last  employment  of  mer- 
cury and  the  salvarsan  injection,  yet  we  know 
through  Moeller's  observations  (*)  that  renal 
damage  following  the  administration  of  mer- 
cury may  be  weeks  in  manifesting  itself,  yes, 
even  months.  A  point  to  be  observed  is  the 
frequency  with  which  chronic  leptomeningitis 
is  to  be  seen  in  connection  with  other  latent  de- 
generations of  an  alcoholic  nature. 

1.  Case  of  Almkuist.  (Muench.  med.  Wochen- 
schr.,  No.  34,  1911.)  Male,  32  years  of  age,  infected 
in  1905.  Treated  during  a  period  of  three  years 
with  eight  courses  of  mercury  (inunctions)  and  six 
or  eight  injections  of  grey  oil.  Since  1908  increase 
of  difficulties.  March  29th,  1910,  fresh  recurrences. 
Until  Oct.  3,  1910,  treated  with  salicylate  of  mer- 
cury injection  and  grey  oil  injections.  Since  the 
Wassermann  reaction  was  still  positive,  Feb.  16, 
1911,  received  an  injection  of  0.6  gram  of  salvarsan. 
Severe  vomiting  during  the  night.  On  the  18th, 
patient  complained  of  headache  and  light  chills. 
Three  days  after  injection  vomiting  started  in 
anew.  In  the  evening  patient  lay  in  his  room  in- 
different to  surroundings.  Face  markedly  cyanotic. 
Notwithstanding  camphor  injections  patient  re- 
mained unconscious,  but,  however,  with  slight  im- 
provement. On  the  fourth  day  pulse  became  ir- 
regular. Albumin  and  hyaline  casts  in  urine.  Dif- 
ficult breathing.  Stiffness  and  paralysis  of  the  left 
arm.  Coma.  This  state  lasted  for  five  days  fol- 
lowing the  injection,  then  came  a  profuse  perspira- 
tory outbreak,  loss  of  the  corneal  reflexes,  tonic  and 
clonic  twitchings  of  the  legs  and  arms,  convulsions. 
Death  on  the  sixth  day. 

Autopsy:  Acute  hemorrhagic  encephalitis, 
chronic  fibrous  splenitis,  chronic  interstitial  neph- 
ritis, swelling  of  the  liver. 


(*)On  Mercurial  Poisoning  and  Angina,  par- 
ticularly Stomatitis  Ulcero-gangrenosa,  together 
with  the  indications  for  and  dose  of  grey  oil. 
Dermatol.  Zeitschrift,  xviii,  Nos.  2  and  3. 

—  124  — 


8ALVARSAN      FATALITIES 


2.  Case  of  Fischer.     (Muench.  med.  Wochenschr., 
No.    34,    1911.)      Male,    40   years   of   age,   with   be- 
ginning maculo-papular  eruption.    For  several  days 
patient    complained    of    headache,    weariness    and 
fever.     Intravenous,  injection  of  0.4   gram  salvar- 
san;  subsequent  light  vomiting  and  chills.     On  the 
following  day  there  was  a  noticeable  Herxheimer 
reaction,  which,  however,  quickly  disappeared.     In 
conjunction  with  the  above,  patient  given  a  course 
of   30    inunctions.      Iodide   of   potassium   not   well 
borne.      (*)      Forty   days   after  the  first  injection 
a  second  was  given.     Same  dose.     Again  vomiting. 
On  the  morning  of  the  third  day  following  the  in- 
jection, patient  began  suddenly  to  feel  bad,  became 
apathetic,  refused  to  answer  questions,  soon  out  of 
his  head.     Then  there  followed  a  period  of  great 
excitement  during  which  it  was   difficult  to  keep 
him   in   bed.     Tonic   convulsions   and   coma.     The 
pulse  became  poor,  temperature  rose  to  40  C.   (104 
Fahr.).    On  the  fourth  day  after  injection,  death. 

Autopsy:  Parenchymatous  degeneration  of  the 
liver  and  kidneys.  Chronic  leptomeningitis  and 
acute  encephalitis.  Edema  and  swelling  of  the 
brain. 

3.  Case  of  Hammer.      (Muench.  med.  Wochen- 
schr.,  No.  30,  1912.)     Jan.,  1911,  patient  showed  a 
primary  lesion  on  the  prepuce.  Wassermann  +  +  +  . 
For  this  reason  patient  received  on  Jan.  17th,  0.6 
gram  salvarsan  intravenously.     Temperature  rose 
to  39  C.  (102  Fahr.).    June  20th,  roseolar  rash  ap- 
peared.    Another  injection  of  0.6  gram  salvarsan. 
Temperature  to  38.4  C.  (101  Fahr.).     Patient  then 
took  a  course  of  inunctions.     In  Nov.,  1911,  on  ac- 
count of  an  "eruption"  patient  took  another  course 
of    30    inunctions.      In    February,    by    reason    of 
"hoarseness"  took  12  more  inunctions.    March  23rd, 
1912,    papules    on    tonsils,    leucoderma,    laryngitis, 
papules  on  the  iaryngeal  borders.     On  the  25th,  0.6 
gram  salvarsan  borne  without  reaction.     Then  18 

(*)  Frequently  here  is  to  be  observed  an  idio- 
syncrasy against  iodide  of  potash,  together  with 
interference  with  its  elimination.  The  patient  re- 
acts with  marked  swelling  of  the  lining  membrane 
of  the  pharynx  and  larynx,  which  leads  to  difficulty 
of  breathing. 

—  125  — 


8ALVAR8 AN      FATALITIES 


inunctions.  Then  again  0.6  gram  of  salvarsan 
which  at  first  was  well  borne,  but -two  days  later 
peculiar  sensations  in  the  ears  were  noticed. 
Temperature  38.1  C.  (100.5  Fahr.).  In  the  even- 
ing marked  twitching  with  outbreak  of  perspira- 
tion. The  following  night  vomiting,  sleeplessness, 
three  pronounced  epileptiform  attacks.  In  urine, 
albumin,  hyaline  casts,  epithelial  cells  and  blood 
corpuscles.  April  15th,  death. 

Autopsy:  Chronic  leptomeningitis.  Punctiform 
hemorrhages  in  brain.  Chronic  endarteritis.  Car- 
diac hyperplasia. 

4.  Case  of  Kannengiezer.  (Muench.  med. 
Wochenschr.,  No.  34,  1912.)  Male,  29  years  of  age, 
infected  in  1910.  Treated  with  salicylate  of  mer- 
cury and  one  subcutaneous  injection  of  salvarsan. 
April  6th,  1911,  specific  angina.  Attacks  of  dizzi- 
ness, paralysis  of  the  lower  fascial  branches,  dif- 
ficulty of  hearing.  April  28th,  intravenous  injec- 
tion of  0.5  gram  of  salvarsan.  Immediately  fol- 
lowing a  course  of  inunctions.  May  10th,  no 
phenomena  except  headache.  May  llth,  another 
injection  of  0.5  gram.  Well  borne,  but  on  follow- 
ing day  headache.  No  albumin  in  urine.  On  the 
third  day  following  injection  patient  seized  with 
convulsions,  together  with  clonic  and  tonic  con- 
vulsive movements.  Bloody  foam  appeared  on 
lips,  then  loss  of  consciousness.  Shortly  follow- 
ing the  attack  patient  became  very  restless;  only 
with  difficulty  could  he  be  kept  in  bed.  Con- 
stantly he  attempted  to  put  his  hand  to  his  head. 
Failed  to  respond  to  external  irritations.  Profuse 
outbreak  of  perspiration.  Venesection  failed  to 
give  any  relief.  Patient  fell  in  coma.  On  the  4th 
day  temperature  38.8  C.  (101.8  Fahr.).  Stiffness 
of  neck  and  cramps  in  arms.  Evening  temperature 
39.3  C.  (102.7  Fahr.).  Clonic-tonic  movements. 
Death  on  the  fifth  day  following  injection.  (*) 

(*)  It  is  noteworthy  that  on  the  day  of  the 
injection,  the  inunctions  had  to  be  stopped  on 
account  of  a  severe  stomatitis  which  fs  always  ac- 
companied by  an  insufficiency  of  the  renal  func- 
tion, and  therefore,  is  to  be  seen  in  uremia.  The 
appearance  of  the  tubular  epithelium  also  points 
to  damage  by  mercury. 

—  126  — 


8 ALVAR8AN      FATALITIES 


Autopsy:  Chronic  leptomeningitis.  Punctiform 
hemorrhages  in  the  brain.  Double  pneumonia. 
Brown  atrophy  and  degeneration  of  the  heart  and 
kidneys.  Granular  condition  of  the  tubular 
epithelium. 

5.  Resembling  "the  above  is  the  case  of  Oltra- 
mare.      (Ann.    des   mal.   v6n.,    Vol.    6,    page   881.) 
Generally  speaking,   the  elimination   of  salvarsan 
may  be  interfered  with  by  aortic  stenosis.     Male, 
48  years  of  age,  very  corpulent,  infected  15  years 
previously.     Previously  treated  with  injections  of 
mercury.     At  the  time  without  manifestations  of 
syphilis.     Heart  and  kidneys  without  change.     Up- 
on the  expressed  wish  of  the  patient,  0.6  gram  sal- 
varsan  was    injected    intravenously.      Well    borne. 
The   following  two   days   patient   went   about   his 
duties.    On  the  third  day  complained  of  light  head- 
ache.    On  the  fourth   day  he   lay   upon   the   floor 
like  a  dead  man.     On  the  fifth  day  in  a  state  re- 
sembling coma,  covered  with  perspiration,  cyanotic 
face,  slow  pulse,  accelerated  breathing,  always  in 
a    convulsive    seizure.      Temperature    40    C.    (104 
Fahr.).     Death  during  the  night. 

Autopsy:  Chronic  leptomeningitis,  stenosis  of 
the  ascending  aorta,  fatty  degeneration  of  the  heart, 
and  chronic  purulent  bronchitis. 

6.  Case  from  Plojesti.      (Ehrlich's  Discussions 
on  Salvarsan,  vol.  II,  page  584.)     Male,  35  years  of 
ago,  old  syphilitic.     One  year  previously  an  intra- 
venous injection  of  0.6  gram  salvarsan  has  been 
well  borne.     Heavy  drinker.     Even  on  the  day  be- 
fore   the    second    injection    indulged    heavily    in 
alcohol.     Patient  should   have  received  0.6   gram, 
but  scarcely   half  the  amount   had   been   injected 
when  he  collapsed  and  died. 

Autopsy:  Pronounced  heart,  liver  and  renal 
changes  of  an  alcoholic  character. 

7.  Case  of  Dr.  St.  in  D.     (Ehrlich's  Discussions 
on  Salvarsan,  Vol.  II,  page  587.)     Male,  aged  17, 
roseola  and   papules   of  the  scrotum  and   tonsils. 
Treated  with  inunctions  up  to  4  grams  each.     On 
June  19th,  received  0.3  gram  salvarsan;  fever  and 
headache    followed.      July    3rd,    0.05    calomel    in- 
jected.    July  5th,  sulphur  bath.     July  10th,   0.01 
gram   of   calomel.     July   14th,    after   the   twenty- 

—  127  — 


8ALVAR8AN      FATALITIES 


seventh  inunction  received  the  second  injection 
of  0.3  gram  salvarsan.  Following  this  patient 
suffered  vomiting,  chills,  headache.  On  the  fol- 
lowing day  also  vomiting  and  headache.  July  16th, 
status  unchanged.  At  noon-time  fainting  spell. 
In  the  afternoon,  stiffness  of  neck,  noticeable 
trismus.  Pulse  60.  In  the  evening  patient  be- 
came confused.  Died  during  the  night. 

Autopsy:  Subpericardial  hemorrhages.  Hy- 
peremia  of  the  brain  and  coverings.  Beginning 
fatty  degeneration  of  the  heart  muscle.  Sclerosis 
of  the  aorta.  Hydrocephalus  internus. 

8.  Case  of  Tremtour.      (Ibid.)     Patient  became 
infected  Nov.  1st,  1911.    Chancre  appeared  on  shaft 
of  penis  on  the  18th.     One  week  later  0.6   gram 
salvarsan  intravenously  injected.     Some  vomiting, 
no  fever.     On  the  26th,  patient  began  a  course  of 
inunctions,  5.0  grams  per  diem.    On  Dec.  6th,  mild 
gingivitis.     Inunctions  stopped.     Dec.  8th,  macular 
eruption  on  the  buttocks.     Dec.  9th,  second  intra- 
venous  injection   of   salvarsan   administered.     No 
reaction.     Three  days   later  patient  became   com- 
pletely unconscious  with  tonic-clonic   convulsions. 
Pulse  regular.     Stiffness  of  the  neck.     Picking  at 
bed-clothes.      Temperature    38    C.     (100.5    Fahr.). 
Dec.  13th.    Again  loss  of  consciousness  and  clonic 
movements.     Pronounced  outbreak  of  perspiration. 
Picking  at  bed-clothes  more  marked.     In  the  even- 
ing beginning  edema  of  the  lungs,  cyanosis.     On 
Dec.  14th,  in  the  morning,  death  took  place.     Be- 
fore death  pulse  dropped  to  32  per  minute. 

Diagnosis:    Meningitis,  inferior  poliocephalitis. 

9.  Case  of  Portner.     (See  text.) 

10.  Case   of   Lesser.      (Berliner   klin.   Wochen- 
schr.,  No.  13,  1912,  page  593.)     Male,  39  years  old, 
infected   fifteen  years  before.     Present  symptoms 
point  to  a  beginning  tabes  dorsalis.    On  Nov.  10th, 
1911,   received   0.5   gram   salvarsan   intravenously. 
Following  this  injection,  vomiting  and  fever.    Nov. 
16th,  0.6  gram  salvarsan  injected.     Also  after  this 
injection,  fever,  vomiting  and  diarrhea.     On  Nov. 
21st,   that   is,   five   days   after   the   last   injection, 
epileptiform  attack,   coma  in  which  patient   died. 

Autopsy:     Leptomeningitis. 

—  128  — 


SALVAR8AN      FATALITIES 

The  following  cases  concern  themselves 
with  nephritis,  in  some  instances  of  a  toxic 
(mercurial)  character,  in  others  of  a  syphilitic 
nature.  In  some"  instances  nitrogenous  reten- 
tion or  uremic  symptoms  were  noticed;  in 
some  anuria  occurred  (see  cases  cited  in  text)  ; 
in  others  still  the  renal  damage  seemed  to  be 
of  a  mild  character,  or  severe  renal  changes 
were  found  at  autopsy,  which  were  unsus- 
pected during  life  because  the  urine  was  not 
examined  with  care. 

1.  Case  from  Berlin.     (Ehrlich's  Discussions  on 
Salvarsan,  Vol.  II,  page  576.)     Male,  26  years  of 
age,  infected  in  August.     On  Sept.  28th,  a  typical 
roseola  appeared  on  breast  and  back.    Hypodermic 
injections    of   salicylate    of    mercury    (0.5    gram). 
Stopped    on    disappearance   of   lesions   about    Oct. 
28th.     Nov.  10th,  appearance  of  new  lesions.     Al- 
bumin in  urine,  strikingly  large  spleen.     The  al- 
bumin  pointed   to   the  character   of   renal   lesion. 
Adopting  the  opinion  that  the  splenic  enlargement 
was  of  a  syphilitic  character,  0.6  gram  salvarsan 
was   intravenously   injected   Nov.   25th.     Vomiting 
after  injection.     On  the  evening  of  Dec.   6th — 11 
days  after  the  injection — complaints  of  headache. 
On  the  morning  of  the  7th,  clonic  convulsions  with 
loss  of  consciousness.     Deep  unconsciousness,  pro- 
nounced trismus.   Temperature  39.5  C.  (103  Fahr.). 
Death  took  place  at  noon. 

Autopsy:  Subacute  parenchymatous  nephritis. 
Acute  encephalitis.  Malignant  granuloma  of  the 
lymph  glands  of  the  entire  lower  aorta  and  spleen. 

2.  Case  of  Caussade  and  Regnard.      (Bull,  de 
la  Soc.  med.  des  Hop.    Session  of  Feb.  10th,  1911.) 
Male,  33  years  of  age,  with  nephritis  and  uremia. 
Emaciated    and    cachectic.      Bedridden    for    three 
years.      Despite   various    modes    of   treatment    al- 
bumin  remained  at  9   grams  pro   litre;    5   grams 
nitrogenous  retention  in  blood.     Quantity  of  urine, 
450   c.cm.   per  diem.     One   injection   of   0.3   gram 
salvarsan  had  no  influence  on  the  course  of  the 

1  on 

i  _  i1 


SALTARS AN      FATALITIES 


disease.      On    the    ninth    day    after    injection    the 
patient   died   of   anuria. 

Autopsy:       Acute     general,     diffuse     nephritis. 
Amyloid  degeneration  of  the  glomeruli. 

3.  Case   of  Ravaut   and   Bith.      (Journal   mcd. 
franc.,  No.  10,  1911.)     Male,  40  years  of  age,  in- 
fected in  April,  1910.     Two  months  later  roseola 
and  patches  in  mouth.     In  October  papular  erup- 
tion on  buttocks  and  legs.    At  the  same  time  mild 
albuminuria,    which   disappeared   with    milk    diet. 
Soon,  however,  albumin  newly  makes  its  appear- 
ance, 15  to  18  grams  per  diem.     General  condition 
good.     Passes  between  2   and   2\'->   litres  of  urine 
daily.     Notwithstanding  energetic  treatment  with 
mercury,   albuminuria    remains   unchanged.     Jan. 
5th,    1911,    patient    received    0.4    gram    salvarsan 
which   was   well   borne.     It   had   no   influence   on 
quantity  of  urine  or  albumin.     On  the  contrary, 
a  slight  edema  of  the  ankles   became  noticeable. 
Jan.  9th,  patient  received  0.7  gram  salvarsan  in- 
tramuscularly.    Immediately  thereafter  uremic  de- 
lirium.    The  next  day  quantity  of  urine  reduced 
to  one  litre  which  contained  5  grams  NaCl  and 
8  grams  nitrogen.    Rapid  increase  of  edema  until  it 
reached  scrotum.     Then  followed   headache,   roar- 
ing noise  in  the  ears,  dyspnea,  delirium,  convul- 
sions,  uremia  and  death  on  Jan.  28th,   under  al- 
most complete  anuria. 

4.  Case  of  Wechselmann.      (See  text.) 

5.  Case  of  Gennerich.     (Praxis  der  Salvarsan- 
behandlung,  page  20,    case    602.)       Infected  Jan., 
1912.     Chancre   and   secondaries   disappear   about 
the  same  time.     From  May  9th  to  June  7th,  1912, 
seven  injections  of  calomel.     After  the  fifth  injec- 
tion a  stomatitis  occurred,  by  reason  of  which  the 
injections   were   stopped    from   May   25th   to   June 
6th.     At  the  same  time  some  albumin   in   urine. 
June  3rd,  0.5  gram  salvarsan  intravenously.     June 
5th,  0.9  gram  neosalvarsan,  and  on  June  7th,  1.08 
neosalvarsan.     Seven  hours  after  the  third   injec- 
tion came  fever,  38.5  C.    (101.3  Fahr.),  clearly  a 
delayed  reaction.    Temperature  normal  next  morn- 
ing,   and    general    condition    somewhat    improved. 
At  four  o'clock  in  the  afternoon  convulsions  and 
loss   of  consciousness.     Venesection,   salt  infusion 

—  130  — 


8 ALVARSAN      FATALITIES 


every  three  hours.  Mental  condition  improved. 
On  following  morning  repetition  of  the  convulsions, 
cyanosis.  Artificial  breathing,  etc.  Death. 

Autopsy:  Pulmonary  embolism.  No  essential 
changes  in  brain.  High-grade  parenchymatous  de- 
generation of  the  renal  epithelium  in  the  con- 
voluted tubules  with  extensive,  far  progressed  nu- 
clear necrosis.  Gennerich  classifies  the  case  as  one 
of  toxic  retention  in  consequence  of  renal  insuf- 
ficiency. 

6.  Case   of   Lugue   Morata.      (Revista   de  Med. 
y  Cirujica  Practicas.     Feb.  28th,  1911.)      Male,  21 
years  of  age,  infected  two  years  before.     Treated 
one  year  with  mercury.     At  the  time  of  examina- 
tion patches  in  mouth  and  pharynx.     Weight  43 
kilograms.       Internal     organs     without     change. 
Urine  normal.     Jan.  31st,  intravenous  injection  of 
0.4  gram  salvarsan.     Three  hours  later  vomiting, 
diarrhea,    outbreak   of   perspiration.     Pallid   face. 
Dry   mouth.     Cyanotic   lips.     Pulse  scarcely   per- 
ceptible.    Complete  anuria.     Catheter  secures   no 
urine  from  bladder.     Delirium,  coma,  and  on  the 
third  day  following  injection  patient  died. 

7.  Case     of     Busse-Merian.        (Muench.     med. 
Wochenschr.,    No.    43,    1112.)      Woman.  )    Condy- 
lomata  and  dirty  ulcerations  on  the  labia  majora. 
As  early  as  Oct.,  1911,  there  was  an  ulcer  on  the 
genitals.     Now  followed  a  thirty-day  course  of  in- 
unctions,  five   grams   each.     Urine   normal.     The 
ulcers   were   now   healing   slowly.     After   quitting 
hospital    patient    began    to    suffer    from    pain    in 
throat.     Gargles   of  no  avail.     Genital   ulceration 
again  making  its  appearance.     Marked  reddening 
of  the  palate,  the  uvula  and  back  portion  of  the 
mouth.     Urine  clear  and  free  from  albumin.     Sp. 
Gr.  1014.     On  Aug.  19th,  intravenous  injection  of 
0.6    gram    neosalvarsan.      Well    borne.      On    Aug. 
27th,  another  injection  of  0.6  gram  neosalvarsan. 
On  the   29th,   light  tremor,   increased   patellar   re- 
flex.     On   the   30th,    tonic-clonic   convulsive   move- 
ments, loss  of  consciousness  and  cyanosis.     On  the 
31st,    coma    and    marked    cyanosis.      Died    in    the 
evening. 

Autopsy:  Extensive  swelling  of  the  epithelium 
of  the  convoluted  tubules.  The  epithelium  of  the 

—  131  — 


8 ALVARSAN      FATALITIES 


glomerular  capsule  is  partially  swollen,  thickened 
and  dequamating. 

8.  Case  Levi.     (Arch.  d'Ophthalm.,  No.  1,  1911.) 
Weak  male,  inveterate  smoker,  with  pyelonephritis. 
Intravenous    injection    of    salvarsan.      Death    in 
three  weeks.    At  autopsy  nothing  found  to  account 
for  arsenical  poisoning. 

9.  Case   of   Marcus.      (Muench.   med.   Wochen- 
schr.,   No.    2,   1911.)      Old,    inveterate   user   of  to- 
bacco,  with   chronic   diarrhea,   cystitis   and   pyelo- 
nephritis.    Death  in  three  weeks  following  the  in- 
jection. 

10.  Case  of  Neuhaus.     (Muench.  med.  Wochen- 
schr..  No.  18,  1911,  page  955.)      Poorly  nourished, 
much  reduced  paralytic,  with  pyelonephritis;   died 
of   heart   failure   five   days   after   an   injection   of 
0.8   gram  salvarsan. 

11.  Case    Ravaut    and    Cain.       (Journal    med. 
franc..  No.  10,  1911.)     Male,  32  years  of  age,  with 
pronounced    tabes,    and    paralysis    of    both    motor 
oculi,    infected    ten    years    before.      Patient,    who 
is  weak,  was  formerly  an  alcoholic.     Albumin  in 
urine.      Heart   and    lungs   without   change.      Mer- 
cury   employed    without    results.      Upon    patient's 
particular  wish  he  received  0.6  gram  salvarsan  on 
March  13th.     Well  borne.     Slight  improvement  of 
the    paralysis    of    the    motor    oculi.      Seven    days 
later  received  another  injection   of  0.6  gram  sal- 
varsan.     Four    days    later,    the    patient    suddenly 
was  seized  with  general  convulsions;   coma  which 
lasted  13  hours.     Death  on  the  fifth  day. 

Autopsy:  Acute  edema  and  congestion  of  the 
lungs.  Sclerotic  gummatous  changes  in  the  liver, 
and  marked  changes  in  the  liver  cells.  Sclerosis 
of  the  connective  tissue  and  vessels  of  the  kid- 
neys. Hemorrhagic  foci  in  the  suprarenals.  Hy- 
peremia  of  the  thyroid  and  pineal  glands. 

12.  Case    of    Sciele.      (St.    Petersburger    med. 
Wochenschr.,  No.  33,  1911.)      Patient  with  severe 
pyelitis  died  shortly  after  injection  of  salvarsan. 

13.  Case  of  Schlasberg.     (Dermatol.  Zeitschrift., 
Oct.,  1912.  )     Male,  47  years  of  age,  with  tertiary 
syphilis,   chronic   nephritis   and   pulmonary   tuber- 
culosis.    In  April,  1908,  he  was  treated  with  seven 
injections   of   grey   oil,   each  containing  0.1   gram 

—  132  — 


SALVA R8 AN      FATALITIES 


of  mercury.  Albumin  and  casts  in  urine.  Sept. 
12th,  1911,  received  an  injection  of  0.4  gram  sal- 
varsan  intravenously.  Following  the  injection  pa- 
tient experienced  prostration,  headache,  tempera- 
ture of  40  C.  (104  Fahr.).  Edema  increasing 
daily.  On  the  20th  day  after  injection  the  patient 
died. 

Autopsy:  Both  kidneys  enlarged.  Chronic 
nephritis. 

[This  list  contains  twelve  other  cases  but  they 
are  of  similar  character  to  those  already  given, 
and  it  is  not  thought  necessary  to  publish  them 
in  this  translation. — Translator.] 

In  the  next  four  cases  a  combined  treatment 
was  employed.  It  is  not  clear  just  what  de- 
ductions we  are  to  draw  from  the  deaths  which 
took  place  after  a  second  or  later  injection. 

1.  Case  of  Hallopeau.      (Bull  de  I'Acad.  Med., 
No.  61,  1911.)     Male,  35  years  of  age,  infected  in 
1902    with    lues.      First    chancre,    then    roseola, 
mucous  patches  and  now  psoriasis  palmaris   and 
plantaris.      Mercury    and    hektin    without    result. 
Injection   of  0.3   gram  salvarsan;    five   days   later 
0.4  gram.     Soon  after  the  second  injection  patient 
complained   of   dryness   in  the  throat  as   well   as 
an  angina  and  congestion  of  the  face.     During  the 
second   night   continued    vomiting.     On   the   third 
day  patient  suffered  from  oppression  and  had  con- 
vulsions.    Pulse  good  and  regular,  urine  clear  and 
abundant.      The    condition    of    the    patient    grow 
steadily  worse.     Several   convulsive  attacks,   roll- 
ing of  head  and  eyes,  tonic  and  clonic  twitching 
of  the  upper  extremities.     Temperature  40  C.  (104 
Fahr.).    Death  in  deep  coma. 

2.  Le  Duigou.     (Bull  et  M6m.  de  la  Soc.  Med. 
des  Hop.     Nov.    17th,   1911.)      Male,   20   years   of 
age,  with  secondary  lues.     Internal  organs  sound. 
Previously    received    20    injections    of    hektargyr, 
also  iodine  pills.     Manifestations  again  appeared 
four  weeks  after  cessation  of  treatment.     Patient 
then  received  three  injections  of  8  drops  each  of 
grey  oil.     Two  weeks  later  injection  of  0.4  gram 

—  133  — 


SALVARSAN      FATALITIES 


salvarsan.  After  the  injection  mild  fever  and 
vomiting,  after  which  condition  was  good.  A 
week  later  the  second  injection  of  0.4  gram  sal- 
varsan. On  the  following  two  days  patient  com- 
plained of  weariness  and  general  feeling  of  dis- 
tress. At  the  same  time,  diarrhea  and  palid  face. 
On  tne  third  day  following  injection  delirium  and 
convulsiform  attacks,  vomiting  of  dark  masses, 
and  finally  death  occurred. 

Autopsy:  Pronounced  congestion  of  all  internal 
organs,  especially  the  intestinal  tract,  the  lungs, 
spleen  and  brain.  In  the  brain  in  many  places, 
punctiform  hemorrhages. 

3.  Gase     of     Klieneberger.        (Deutsche     med. 
Wochenschr.,    No.    36,    1912,    page    1691.)      Wait- 
ress,   25    years    of    age.      Six    months    pregnant. 
Maculo-papular    eruption,    large    condylomata    on 
vagina    and    anus.      Wassermann    positive.      In- 
unction course,  four  grams   daily;    every  seventh 
day  an   injection    (0.1)    of  salicylate   of  mercury. 
On    March    29th,    0.2    gram    salvarsan    intramus- 
cularly;   on   April   3rd,    1.2   grams   intravenously. 
Rapidly  disappearing  urticaria  followed  injection. 
A  stomatitis  recurred  during  the  mercurial  course. 
May  22nd,  0.  6  gram  salvarsan  intravenously.     On 
the   following   day   moderate   indifference   to   sur- 
roundings  and   apyrexia.      May   24th,   tonic-clonic 
movements.     Unconsciousness.     Treatment  for  ec- 
lampsia according  Stroganoff.     On  the  25th,  deep 
coma,    sterterous    breathing.      Lumbar    puncture 
gave  a  clear  fluid  with  low  pressure.    Lymphocytes 
and  albumin.     Death  at  midnight. 

Autopsy:  Extensive  fresh  soft  areas  on  both 
Sides  in  brain,  also  small  hemorrhages  in  abund- 
ance. Hypostatic  congestion  in  lungs  just  begin- 
ning. 

4.  Case  of  Dr.  M.  in  C.     (Ehrlich's  Discussion 
of  Salvarsan,  Vol.  II,  page  588.)     Male,  38  years 
of  age,  tertiary  syphilis.    Treated  for  a  long  period 
with  mercury  without  results.    Dec.  27th,  0.5  gram 
salvarsan    intravenously.      Eight    days    later    0.5 
gram  salvarsan  again  injected.     Well  borne.     On 
the  evening  of  the  following  day  loss  of  conscious- 
ness.    Lumbar  puncture,   salt   infusion,   camphor, 
etc.     During  the  night  epileptiform  attacks,  death. 

—  134  — 


SALVARS AN      FATALITIES 

1.  Cases  in  which  mercury  was  not  given 
at  the  same  time  with  the  salvarsan  and  in 
which  the  urine,  remained  free  from  albumin, 
and  which,  however,  die  after  one  or  two  in- 
jections of  salvarsan,  are  but  rarely  encoun- 
tered. In  the  text  of  this  work  I  have  analyzed 
the  case  of  Balzer-Condat.  In  Pinkus'  case 
the  status  lymphaticus  could  be  considered  as 
underlying  the  failure  of  elimination.  In 
Ravaut's  case  oliguria  seems  to  have  been  ex- 
hibited. In  F.  Lesser's  case,  leptomeningitio 
(see  above). 

1.  Case    of    Pinkus.       (Dermatol.    Zeitschrift, 
Aug.,  1912.)     Girl,  19  years  of  age,  infected  when 
14.    At  that  time  had  a  course  of  inunctions.    Re- 
peated in  1910.    Nov.  29th,  1911,  papules  at  vaginal 
entrance.    Cervical  gonorrhea.    On  the  morning  of 
Dec.   1st,   she   received   0.3   gram  salvarsan   intra- 
venously.    Headache   followed   injection.     On   the 
6th,  received  second  injection  of  0.5  gram.   Vomit- 
ing followed  this  injection.    On  the  7th,  complained 
of   abdominal    pains    (diseased    adnexa).      No    al- 
bumin.    On  the  evening  of  the  8th,  she  was  seized 
with  an  acute  delirious  attack,  with  shrieking  and 
manifestations   of   fear.     Staring  eyes,   pupils   re- 
spond    promptly.       Unconscious.       Pulse     strong, 
rapid.    On  the  9th,  deep  coma,  convulsions,  stringy 
pulse,  camphorated  oil.    Temperature  41.5  C.  (106.7 
Fahr.).      Heart    attack.      Camphorated    oil    again. 
Temperature  42  C.    (107.6  Fahr.).     Cheyne-Stokes 
breathing.     Death. 

Autopsy:  Hyperemia  of  lungs.  Internal  organs 
without  change.  Many  punctiform  hemorrhages  in 
•me  lenticular  nucleus. 

2.  Case    of    Marschalks-Vesprzemy.      Given    in 
text. 

The  case  of  Spiethoff  stands  entirely  by  it- 
self. The  urine  showed  a  marked  sugar  con- 
tent in  the  presence  of  encephalitis  hemorr- 
hagica.  The  renal  condition  was  not  given. 

—  135  — 


SALVARSAN      FATALITIES 


Case  of  Spiethoff.  (Muench.  med.  Wochenschr., 
No.  21,  1912.)  Male,  19  years  of  age,  in  primary 
stage.  Wassermann  negative.  On  Oct.  3rd,  1911, 
patient  received  an  intravenous  injection  of  0.5 
gram  salvarsan  in  a  weakly  acid  solution.  On 
Oct.  10th,  another  injection  of  0.5  gram.  Both  in- 
jections well  borne,  aside  from  moderate  fever. 
Oct.  llth,  patient  felt  well  enough  to  leave  the 
hospital.  In  the  afternoon  headache.  On  next 
day  loss  of  consciousness,  convulsions,  poor  pulse. 
In  the  evening  patient  returned  to  hospital. 
Tracheal  breathing  with  the  mouth  open.  Tem- 
perature 39.3  C.  (102.7  Fahr.).  Urine  free  from 
albumin,  but  Nylander  strongly  positive.  Stiff- 
ness of  neck,  clonic  movements.  Foam  appeared 
at  lips.  Lumbar  puncture  shows;  pressure  180,  no 
cellular  increase,  Nonne  +  +  ++.  One-half  hour 
after  entrance  of  patient  into  hospital  death  oc- 
curred. 

Autopsy:  Edema  of  the  spinal  cord,  especially 
in  upper  part.  Nothing  else  of  a  pathological 
nature  to  be  found  either  macro-  or  microscopically. 

3.  Now  comes  cases  dying  of  acute  yellow 
atrophy  of  the  liver,  in  which  the  dependence 
of  death  upon  salvarsan  is  highly  3uspicious. 
(See  text.) 

1.  Case  of  Hirsch.  ^Muench.  med.  Wochenschr., 
No.  33,  1911.)  Woman,  23  years  of  age,  broad 
condylomata  of  the  labia  majora,  erosions,  within 
vagina,  inguinal  adenitis,  leucoderma  colli.  Dec. 
29th,  injection  of  0.3  gram  salvarsan;  well  borne. 
Then  six  injections  each  of  0.1  salicylate  of  mer- 
cury, and  on  Feb.  3rd,  1912,  patient  was  given  an- 
other injection  of  the  mercurial  salicylate.  After 
two  months,  April  19th,  the  patient  suddenly  be- 
came unconscious,  rigid,  widely  open  pupils,  con- 
vulsiveform  twitchings  of  the  entire  musculature, 
slow  tense  pulse,  considerable  icterus.  Death  on 
April  20th,  in  coma. 

Case  of  Hoffman.  (Muench.  med.  Wochenschr., 
No.  33,  1911.)  Male,  15  years  of  age,  with  syphilitic 
iritis  of  the  right  eye.  Wassermann  and  Stern 

—  136  — 


8 ALVARS AN      FATALITIES 


positive.  Therefore  a  course  of  inunctions.  Dur- 
ing these  inunctions  there  appeared  an  iritis  of 
the  left  eye.  No  results  from  treatment  with  mer- 
cury; on  the  contrary,  hot  applications  effected 
some  good.  On  Feb.  21st,  1911,  patient  was  given 
an  injection  of  0.3  gram  salvarsan  which  was  well 
borne.  On  Feb.  27th,  given  an  intramuscular  in- 
jection of  0.3  gram;  also  well  borne.  On  April 
8th,  upon  dismissal,  a  gastro-intestinal  catarrh  was 
discovered,  on  account  of  which  patient  was  re- 
entered.  April  13th,  an  icterus  developed  with  fre- 
quent vomiting,  prostration  and  headache.  These 
phenomena  increased  daily.  Pulse  55;  loss  of  con- 
sciousness; death  on  June  5th. 

Autopsy:  Acute  yellow  atrophy  of  the  liver  with 
moderate  ascites. 

3.  Case  of  Lane.     (Bri.  Med.  Jour.,  Sept.  23rd, 
1911.)     Male,  29  years  of  age,  malignant  syphilis 
since  1909.     Once  during  mercurial  treatment  did 
patient  show  improvement.    Recurrences  February, 
1910  (ulcerations  of  both  cheeks,  lips  and  palate). 
February   22nd,   received   an  injection   of   0.5   sal- 
varsan;   shortly    thereafter    vomiting    and    coma. 
Two    days   later    a   pronounced    icterus    appeared, 
the  patient  taking  on  a  brownish  black  color  from 
head  to  foot.     March  1st,  delirious;    died  the  fol- 
lowing day. 

4.  Case  of  Rille.     (Muench:  med.  Wochenschr., 
No.  11,  1911.)      Male,  23  years  of  age,  secondary 
and  tertiary  syphilis  on  account  of  which  received 
on   Sept.   7th,   0.7   gram  salvarsan.      In   November 
icterus    and    severe    hemorrhages    from    the    nose 
took  place.     Nov.  5th,  death  occurred,  just  as  pa- 
tient was  about  to  be  sent  to  hospital. 

Autopsy:  Acute  cirrhosis,  interstitial  nephritis, 
fatty  degeneration  of  the  liver.  Arsenic  demon- 
strable in  liver. 

5.  Case  of  Severin  and  Heinrischsdorff.     (Zeit- 
schrift  fuer  klin.  Med.,  Vol.  76,  page  138.)     Male, 
30  years  of  age,  acrobat.     May,  1911,  chancre,  pig- 
mentation, adenitis,  angina.    Wassermann  -K    One 
injection  of  mercury  in  olive  oil,  15%    (0.05  gram 
mercury).    June  10th,  intravenous  injection  of  0.6 
gram   salvarsan.     Chills,    diarrhea   and   vomiting. 
On    the    14th,    another    injection    of    salvarsan. 

—  137  — 


SALVARSAN      FATALITIES 


Headache.  August  llth,  0.6  gram  salvarsan. 
Wassermann  +.  In  evening  mild  icterus;  next 
morning  entire  body  yellow.  Headache,  loss 
of  appetite,  vomiting.  In  the  urine,  hyaline, 
granular  casts,  epithelial  cells,  no  leucin  or 
tyrosin.  Liver  enlarged,  sensitive  to  pressure. 
Death  on  Sept.  6th. 

Autopsy:  Arsenic  in  liver;  less  so  in  spleen. 
Chronic  yellow  atrophy  of  the  liver.  Hemorrhages 
in  endo-  and  pericardium.  Hemorrhages  in  both 
lower  lobes.  Hyperemia  and  edema  in  both  under 
and  right  upper  lobes.  Hemorrhages  in  stomach 
and  bowels.  Pronounced  icterus  of  the  kidneys. 
Chronic  enlargement  of  the  spleen. 

6.  Case  of  Severin  and  Heinrichsdorff.  (Ibid.'t 
Female,  29  years  of  age.  Infected  in  1909.  Arsan, 
lod.  June,  1910,  72  grams  of  mercurial  ointment. 
In  Sept.,  1910,  the  same.  On  account  of  persist- 
ence of  luetic  manifestations  patient  received  0.35 
gram  salvarsan  intravenously  on  Dec.  1st.  Head- 
ache, diarrhea,  disappearance  of  the  manifesta- 
tions. Dec.  6th,  1910,  0.6  gram  salvarsan  and  1.5 
indipin  intramuscularly.  Dec.  16th,  0.4  gram.  Was- 
sermann negative.  Jan.  21st,  0.6  gram  salvarsan 
intravenously.  Beginning  March  13th,  and  until 
May  2nd,  four  injections  of  mercury.  June,  1911, 
pregnant.  Swelling  of  the  limbs,  coughing.  In- 
strumental abortion  produced  Sept.  10th,  1911. 
Vomiting,  diarrhea,  bloody  mucous  discharges  from 
bowels.  Icterus.  Sept.  21st,  received  in  the  hos- 
pital with  a  high-grade  icterus,  ascites,  etc.  Urine: 
Albumin,  bilirubin,  abundant  deeply  yellow  hyaline 
and  granular  casts,  epithelial  cells,  but  no  tyrosin 
or  leucin.  Death  Sept.  28th.  In  the  liver  only 
slightest  traces  of  arsenic  could  be  demontrated. 

4.  We  now  come  to  salvarsan  fatalities 
which  by  reason  of  inexact  observation  pos- 
sess no  scientific  worth.  As  a  rule  these  pa- 
tients had  organic  lesions. 

1.  Case  of  Bloch.  (Korrespondenzheit  fuer 
Schweizer  Aerzte,  No.  3,  1911.)  Patient  with  ad- 
vanced cirrhosis  of  the  liver  and  severe  circulatory 

—  138  — 


SALVARSAN      FATALITIES 


disturbances,  died  shortly  after  an  intramuscular 
injection  of  salvarsan  in  neutral  suspension. 

2.  Case  from  -London.     Male,  47  years  old,  in- 
veterate   smoker,    markedly    cachetic.      Intramus- 
cular injection  of  0.5  gram  salvarsan.     Condition 
grew  worse  until  death.     Nothing  of  exactness  de- 
termined. 

3.  Case  of  E.  Frank.     (Berliner  klin.  Wochen- 
schr.,  No.  31,  1911.)     Male,  infected  fifteen  years 
previously,    suffered    for   two   years    from    mental 
weakness.     At  times  excited,  at  times   depressed. 
Wassermann    of    blood    and    cerebro-spinal    fluid 
positive.    Oct.  15th,  injection  of  0.3  gram  salvarsan. 
Memory  for  certain  things  rapidly  improved.     Ten 
days  later  another  injection  of  0.3  gram.  Wasser- 
mann negative.    Five  weeks  later  patient  died  sud- 
denly  in   coma.     Wassermann   had  again  become 
positive. 

Autopsy:     Several  indistinct  lesions  adjacent  to 
the  vessels  of  the  cortex. 

4.  Case    of   Gaucher.      (Mentioned    by   Lesser, 
Berliner  Min.  Wochenschr.,  No.  13,  1912,  page  593.) 
Male,  48  years  old,  infected  for  fifteen  years.   Aug. 
17th,    1911,    received   an   intravenous   injection   of 
0.6  gram  salvarsan.    On  Aug.  21st,  after  preceding 
vomiting    and    prostration,    occurrence    of    convul- 
sions  and    loss   of   consciousness.     Coma.     Death 
on  the  22nd,  five  days  after  the  injection. 

Autopsy :     Leptomeningitis. 

5.  Case   of   Gaucher.      (Bull,   de   TAcad.   m£d., 
Feb.  6,  1912.)     Male,  24  years  of  age,  treated  with 
mercurial    pills.      Infected    two    years    previously. 
Following  professional  advice  patient  received  in 
Paris   in   a   period   of   thirteen   days,   three  injec- 
tions of  salvarsan,  each  0.3  gram.     After  each  in- 
jection vomiting  and  fever.    On  the  sixth  day  after 
the  last  injection  became  seized  with  convulsive 
attacks  which  followed  severe  headache.    These  re- 
peated   themselves.      Patient    fell    into   coma   and 
on  the  seventh   day  after  the  last  injection,   im- 
mediately after  a  transitory  improvement,   death 
occurred. 

6.  Case  of  Guilain  and  Ravant.      (Bull,  de  la 
Soc.  M6d.  des  Hdp.,  Nov.  4th,  1910.)     Woman,  28 
years  of  age,  secondary  syphilis   and  hemiplegia. 

—  139  — 


SALVARSAN      FATALITIES 


Injection  of  0.45  gram  salvarsan  without  any  re- 
sult.     Death    in    seven    days. 

Autopsy:     Small,  soft  foci  in  brain. 

7.  Case  of  Dr.  H.  in  B.    (Martius).     (Muench. 
mcd.  Wochenschr.,  No.  20,  1911.)      Male,  41  years 
of  age,  infected  13  years  before.     Since  April,  1910, 
pronounced    paralysis.      In    obedience    to    the    af- 
flicted man's  wish,  he  was  given  an  injection   of 
salvarsan.     Thereafter   slight   improvement.     Oct. 
19th,   1910,   further  complicated   by  a   pneumonia. 
Death  the  next  day  in  consequence  of  heart  weak- 
ness. 

Autopsy:  Hypertrophy  of  the  heart,  croupous 
pneumonia  (lower  lobes). 

8  to  10.  Cases  of  Hamel.  (Verein  deutscher 
Naturforscher  und  Aerzte,  Koenigsberg. 

8.  Aortitis    syphilitica    and    aortic    aneurysm. 
Death  in  three  weeks. 

9.  Severe  myelitis  ascending.    Death  in  six  days. 

10.  Luetic  meningitis.     Death  shortly  after  in- 
jection. 

[Since  it  is  not  believed  that  the  inclusion  here 
of  the  remaining  27  cases  of  this  group  would 
serve  any  distinct  purpose,  they  are  omitted. — 
Translator.] 

The  following  are  cases  of  very  severe  in- 
fections or  of  serious  chronic  illnesses.  It  is 
not  possible  to  charge  salvarsan  with  being 
the  cause  of  death  in  these  instances. 

1.  Case  of  Dind.     (Revue  Med.  de  la  Suisse  K 
romande,  No.  1,  1912.)     Patient  had  large  lympho- 
sarcoma.     Death  fifteen  days  after  injection  of  0.4 
gram   salvarsan   with   edema   of    the   tongue    and 
larnyx. 

2.  Case    of    Iverson.      (Iverson,    Discussion  on 
Salvarsan,    page    342.)      Woman,    alcoholic,    hys- 
terical, suffering  from  recurring  fever,  treated  fif- 
teen years  previously  with  mercury.     She  received 
0.3    gram    salvarsan    intramuscularly.      Fourteen 
hours    later   the   spirochetes   which   at   first   were 
found  in  the  blood  in  abundance,  had  disappeared. 
On  the  fourth  day  the  temperature,  hitherto  nor- 

—  140  — 


SALVARSAN      FATALITIES 


mal,  rose  to  38  C.  (100.4  Fahr.).  .At  the  same 
time  patient  appeared  to  have  a  double-sided  bron- 
cho-pneumonia. On  the  head  there  was  a  hemorr- 
hagic  eruption  which  at  first  resembled  that  of 
scarlet  fever.  Later  there  appeared  acute  neph- 
ritis, edema  of  the  upper  part  of  the  body,  swell- 
ing of  the  liver  and  hemorrhages  into  the  skin, 
which  the  reporter  looked  upon  as  a  condition  of 
idiosyncrasy. 

Autopsy:  Marked,  well  advanced  general  arterio- 
sclerosis, myocarditis,  fatty  liver,  and  other  pro- 
nounced changes  of  the  vital  ograns. 

3.  Case  of  Leede.     (Muench.  med.  Wochenschr., 
No.    22,    1911,    page    1185.)      Patient    showed    40% 
hemoglobin,  red  blood  corpuscles  1,400,000.   Patient 
had  worked  up  to  within  a  short  time  of  admission. 
He  received  an  intragluteal  injection  of  0.4  gram 
salvarsan.     Minimal  rise  of  temperature.     During 
the    next    two    weeks  became  worse — hemoglobin 
it>%,  red  blood  corpuscles  900,000.    With  this  came 
dizziness,  buzzing  in  ears,  vomiting  and  rapid  de- 
cline.     Treated    with    iron-arsenical    combinations 
and   fresh   air   with   result   that   in   three   months 
hemoglobin  reached  80%.     He  was  thereupon  dis- 
missed.     In    four    months    recidives,    hemoglobin 
50%.     At  this  juncture  patient  received  0.5  gram 
salvarsan.    Thereafter  followed  striking  declension 
with  death  in  20  days. 

No  autopsy. 

4.  Case  of  Moutot.     (These  de  Chevalier-Seyvet, 
page  42,  Lyons;   1911.)     Woman  with  epithelioma 
of  the  tongue.     Operated  on  Feb.  2nd,  1910.     Re- 
currence.    On  Feb.  llth,  intravenous  injection  of 
0.6  gram  salvarsan  in  alkaline  solution.     The  next 
day  patient  complained  of  dryness  in  throat.     The 
17th,  hemorrhage  and  death. 

5.  6.     Cases   seen   by   Schreyer   in   Tien   Tsin, 
China.     Suffering  from  tuberculosis,  both  quickly 
died  following  the  injection.     The  reporter  attri- 
buted death  in  a  measure  as  due  to  the  drug. 

7.  Case  of  von  Tordey.  (Dreyfus,  page  11.) 
Female  with  severe,  hopeless  anemia  and  tumor 
of  the  spleen,  received  an  injection  of  0.3  gram 
subscapularly.  After  slight  improvement  patient 

—  141  — 


8ALVAR8AN      FATALITIES 

became  worse  and  died  on  the  ninth  day  following 
injection.     Patient  was  very  cachetic. 
Autopsy:     Splenomegaly. 

8.  Case  of  Treupel  and  Levi.     (Muench.  med. 
Wochenschr.,  No.  5,  1911.)     Girl,  15  years  of  age, 
tumor  of  the  brain   and   hydrocephalus   internus. 
No  symptoms  of  lues.     Wassermann  negative.     In 
deference  to  the  wishes   of  the   parents   and   the 
physician  in  charge,  she  was  given  an  intramus- 
cular injection  of  0.5  gram.     At  first  well  borne. 
After  three  weeks  died  suddenly  as  a  consequence 
of  paralysis   of  respiration. 

Autopsy:  Glioma  cerebelli;  hydrocephalus  in- 
ternus. 

9.  Case   of    Tscherne-Schwartz    and    Halpern. 
(Roussky  Vratsch,  Mar.,  1912.)     Death  took  place 
three    hours    after    intravenous    injection    of    0.35 
gram.     Patient  had  typhoid  fever.     Death  resulted 
from    heart    failure    following    transitory    convul- 
sions. 

10.  Case    of    Tuchinsky.       (Roussky    Vratsch, 
March,  1911.)     Death  occurred  six  hours  after  an 
intravenous  injection  of  0.5  gram  salvarsan  in  the 
case  of  a  malarial   patient.     Death   due  to   heart 
paralysis.    At  autopsy,  acute  nephritis. 

From  the  literature  of  reported  cases  of 
deaths,  one  can  see  that  such  fatalities  form  a 
variegated  group  without  showing  a  distinct 
type.  In  only  the  smallest  number  of  these 
cases  can  death  be  attributed  directly  to  salvar- 
san. The  marked  differences  in  the  clinical 
pictures  of  fatal  cases,  among  which  encepha- 
litis hemorrhagica  is  a  frequent  type,  show 
that  salvarsan,  insofar  as  the  greater  number 
of  cases  are  concerned,  is  but  an  indeterminate 
factor  and  not  a  distinct  cause  of  death.  Thus 
no  uniform  explanation  fitting  all  cases  can 
be  given.  A  glance  at  the  reports  of  fatalities 
is  sufficient  to  show  how  recklessly  salvarsan 

—  142  — 


SALVAR8 AN      FATALITIES 

was  employed  at  first,  and  it  is  certain  that 
many  of  the  fatalities  could  have  been  avoided. 

I  am  well  aware  of  the  fact  that  this 
presentation  is  not  without  defects,  and  that 
I  had  to  use  a  wide  variety  of  conclusions 
and  deductions.  But  in  view  of  the  eminently 
practical  lessons  taught  by  the  fatal  cases,  and 
in  spite  of  obvious  defects,  I  consider  it  my 
duty  to  offer  these  observations  in  order  to 
impress  upon  those  using  salvarsan  the  need 
for  greater  precautions. 

These  precautions  are : 

1.  The  most  exact  technique. 

2.  A  dose  of  the  drug  carefully  adapted  to 
the  individual  case. 

3.  Careful  observation  of  the  urinary  se- 
cretion when  employing  salvarsan;  resorting 
to  the  most  exact  chemical  and  microscopical 
examination  of  the  urine.     This  holds  good 
particularly  when  the  combined  treatment  is 
employed. 

4.  The    conjoint    use    of    salvarsan    with 
heavy  mercurial  treatment  is  dangerous!     If 
one  will  use  the  combined  treatment,  then  give 
mercury  very  carefully  many  days  after  the 
last  salvarsan  injection,  but  never  reverse  this 
rule ! 

5.  Take   into   careful   consideration   every 
general  reaction  or  rise  of  temperature,  follow- 
ing the  use  of  salvarsan,  and  make  a  full  in- 
vestigation of  the  causes  of  such  effect. 

Only  by  close  obedience  to  the  above  will  it 
be  possible  to  begin  the  more  refined,  scientific 
investigation  of  apparently  so  simple,  but  in 
reality  highly  complicated,  an  occurrence  as  a 
salvarsan  fatality. 

—  143  — 


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